Breast Cancer Survivors

Chemo Secrets From a Breast Cancer Survivor

Undergoing chemotherapy can be one of the most terrifying things that you go through in your life. One of the most frightening things about chemotherapy is the lack of real information that most people have about it, and the unknown makes it so much more frightening as a result. This eBook, written by a young cancer survivor gives you the real story about what chemo is all about. The most valuable information you can get about chemotherapy is from someone that has already experienced it. This PDF eBook allows you to download and read it as soon as your order it. You can begin your journey of reassurance as soon as you want! Because that's what this is about: chemo does not have to be a terrifying unknown! Other people have gone through it before, and want to help you through it as well! This eBook is the guide through chemo that many people wish they could have had, and now you can have it yourself! Read more here...

Chemo Secrets From a Breast Cancer Survivor Summary

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Author: Nalie Augustin
Official Website: nalie.ca
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The Rising Incidence of Breast Cancer

Breast cancer is a serious, potentially lethal disease. Its incidence has been rising steadily since 1950, most significantly in postmenopausal women. Approximately 183,000 new cases are diagnosed in the United States each year, comprising 31 percent of all cancers. Of these cases, over 40,000 will die. In fact, breast cancer is the leading cause of death in women forty to fifty-nine years old. An American woman today has a one in eight (12.5 percent) cumulative risk of developing breast cancer in her lifetime1 (table 1.1). Many theories have been proposed to explain the increased incidence of breast cancer in modern times. Some of the data may reflect the increase in life expectancy. The increase in reported cases may also reflect the increase in awareness and in screening programs for early cancers. However, these explanations do not fully account for the increased incidence. Researchers and clinicians agree only that breast cancer is a complex disease that reflects the interplay of...

Sporadic vs Inherited Breast Cancer

In approximately 70 percent of cases, there is no family history of breast cancer. Those cancers are sporadic. The remaining 30 percent have a close family member (mother, sister, aunt) who also has the disease, suggesting that their susceptibility to developing the disease is inherited. However, a patient may have a close family member who is also affected and yet she may have sporadic disease. Only 5 10 percent of all breast cancer patients carry a known mutation that greatly enhances their chance of developing the disease. Sporadic breast cancers may also involve defective genes that enhance susceptibility, but to date these gene defects have not been clearly identified, nor are they known to be inherited. Although only some cancers are inherited, all involve damage to genes, as I will describe in chapter 2. Therefore, all cancers are genetic diseases.

Neoadjuvant Chemotherapy

The use of systemic chemotherapy earlier in the course of treatment, an effective strategy in some malignancies, has been explored to a small degree in prostate cancer. The objectives of neoadjuvant chemotherapy are to downstage the cancer, decrease the incidence of positive surgical margins, and eliminate micro-metastases. In addition, chemotherapy may eradicate both androgen-independent clones and androgen-sensitive clones, the latter by synergizing with hormonal ablation. Several pilot neoadjuvant chemotherapy trials have now been reported, and suggest that from a surgical standpoint this is a feasible approach (Table 4.4). Pettaway et al. 38 treated patients with high-risk localized disease with 12 weeks of ketoconazole and doxorubicin alternating with vinblastine and estramustine (KAVE) and androgen ablation followed by radical prostatectomy (RP). The primary end point, a 20 pathological complete response (pCR), was not achieved, but there were fewer positive margins. Clark et...

The Role of Sex Age Hormonal Status and Ethnicity on the Biology of Breast Cancer

As noted in chapter 1, men are also susceptible to breast cancer, and it can be just as deadly. The disease follows a similar course, but since men are often unaware that they can get breast cancer they may delay seeing a doctor when they find a suspicious lump, and therefore may be diagnosed too late for effective treatment. Age is the greatest risk factor for developing breast cancer, but tumors in post-menopausal women are sometimes less aggressive than in those who are pre-menopausal. A role for female sex hormones in breast cancer has long been suspected because women are far more susceptible than men. Early menarche and late menopause, which lengthen the period of exposure to sex hormones, increase the risk for breast cancer. The age at which a woman has her first child, the number of pregnancies, and whether she breast feeds may also be risk factors and are related to hormonal status. The amount of breast tissue available may be a factor, but small-breasted women are at similar...

Chemotherapy in Prostate Cancer

Prostate cancer is now most frequently diagnosed malignancy and the second leading cause of cancer-related death 1 . Death rates have increased over the past 20 years and mortality may approach that of lung cancer within 15 years 2 . For patients with advanced disease, the response rate to hormonal therapy is about 80 , but this is not durable, and all patients will eventually develop hormone-refractory prostate cancer (HRPC) 3 . Chemotherapy has been shown to have palliative benefit in symptomatic HRPC, but has not yet been demonstrated to prolong survival. Median life expectancy for patients with HRPC is only 12 to 18 months, underscoring the urgent need for new therapeutic approaches 4 . Historically, the role of aggressive systemic chemotherapy in HRPC had been questioned because elderly patients with poor marrow reserve, concomitant illnesses, and poor performance status tolerated it poorly. Coupled with this, chemotherapy trials before 1991 reported response rates of only 5 . In...

How Does Breast Cancer Kill

Once a cancer has spread, it is difficult to control. Treatments such as surgery, chemotherapy, or radiation may reduce the mass of the tumor, but metastatic cells may remain in lymph nodes or elsewhere and eventually resume their rampage. Some cells develop resistance to chemotherapy or radiation. Those cells have a selective advantage and will continue to grow. Eventually, vital organs are destroyed and the patient dies of organ failure or hemorrhage. Cancer patients often develop fatal infections. White blood cells, which are critical for fighting infections, are made in the bone marrow. As mentioned above, chemotherapy destroys all fast-dividing cells including those in the marrow. The patients are left immunosuppressed and are susceptible to a variety of infections that people with intact immune systems normally overcome. The marrow may also be destroyed by direct invasion by the tumor cells. It is therefore extremely important for breast cancer or any fast-growing cancer to be...

Intravesical Chemotherapy and Recurrence Progression Rates

Intravesical chemotherapy agents were traditionally administered as delayed bladder instillations initiated at least 1 week following transurethral resection of the tumor and continued for up to 6 weeks. Such regimes were originally intended as prophylaxis against new occurrences, and had been demonstrated in many series to effect significant reductions in the short-term tumor recurrence rates. Early recurrence rates (within 1 year) for low-grade (G1 or G2), low-stage (pTa) superficial tumors can be reduced by up to 33 using anthracyclines 41 and 33 to 50 using MMC 42 , although these rates are adversely affected by increasing tumor stage and grade 43 .Unfortunately,good initial responses have proven less durable with prolonged tumor surveillance. In a review of 2861 patients enrolled in controlled studies up to 1992 42 , the long-term reduction in tumor recurrence averaged only 17 . Indeed, in those followed 5 years or more, the recurrence rate increased to that achieved using...

The Search for the Breast Cancer Gene

Unlike retinoblastoma or AT, which are caused by a defect in a single gene, breast cancer is multifactorial it is caused by the interaction of genes and the environment. Most cases are sporadic, occurring in women who have no family history of the disease and no obvious risk factors. At least 30 percent of patients have some family history, however, and 5 10 percent of patients have close relatives with the disease. Clusters of breast cancer cases within an immediate family have been observed for many years. A large study by the National Centers for Disease Control helped identify specific characteristics of inherited breast cancers Most are diagnosed at an early age (less than forty years old). Many are bilateral, that is, they occur in both breasts. The risk to an individual appears to rise with the number of affected first-degree relatives (mother, daughter, sister). Some patients, or their close relatives, also suffer from ovarian cancer.

Implications for Current Breast Cancer Investigations

Clinical and epidemiological studies have revealed a close association between breast-cancer risk and the cyclical exposure of the mammary gland to ovarian sex steroids that occurs during the premenopausal years (reviewed in 151). This correlation is further substantiated by the fact that inhibition or reduction of such steroidal exposure, (e.g., after oophorectomy, and in late menarche and early menopause), has been demonstrated to markedly reduce breast-cancer risk (152-155). The increase in breast cancer observed with advancing age (Fig. 10) is currently hypothesized to arise from ovarian sex-steroid-induced proliferation of the mammary epithelial cell, which allows for the occurrence and aggregation of genetic changes throughout the reproductive years that result in breast cancer in later life (156). With a primary correlate of breast-cancer risk linked with the cyclical exposure of the mammary epithelial cell to ovarian sex steroids, breast-cancer prevention treatments based on...

Chemotherapy for Bladder Cancer

Transitional cell carcinoma (TCC) of the urinary bladder is the second most common genitourinary malignancy. Each year, over 73,000 new cases are reported in Europe and over 56,000 new cases in the United States. A substantial percentage of these patients develop metastases despite initial management for presumed localized disease, whereas others have metastases at the time of presentation. Once metastasis occurs, the median survival for patients with TCC is approximately 1 year. To improve this poor survival rate, intense efforts over the past two decades have focused on the development of active chemotherapeutic regimens for use in this disease, both in the perioperative setting and in the setting of advanced disease. Chemotherapy for advanced disease is discussed here first because of its impact on the management of early-stage disease.

Postchemotherapy Surgery in Metastatic Transitional Cell Carcinoma

The importance of postchemotherapy surgery in the setting of minimal residual disease after achieving a near complete response to chemotherapy has been highlighted in several analyses 45-47 . In a series of 203 patients treated on five trials with MVAC, 50 patients underwent postchemotherapy surgery for suspected or known residual disease 45 . Seventeen patients had no viable tumor found at postchemotherapy surgery. In three patients, the residual disease was unresectable. In the remaining 30, residual TCC was completely resected, resulting in a complete response to chemotherapy plus surgery. Of these 30 patients, 10 (33 ) remained alive at 5 years, similar to results attained for patients achieving a complete response to chemotherapy alone. Optimal candidates for postchemotherapy resection of residual disease had prechemotherapy disease limited to the primary site or lymph nodes.

Adjuvant Chemotherapy

As with neoadjuvant chemotherapy, administration of chemotherapy after surgery is associated with potential advantages and disadvantages. Foremost, an adjuvant approach allows the administration of chemotherapy to be based on pathologic stage. Given the inaccuracies in clinical staging, this avoids overtreat-ment of patients who are estimated to have a reasonable outcome from surgery alone. Administration of chemotherapy after surgery also prevents delays in carrying out potentially curative surgery. The major disadvantages associated with adjuvant chemotherapy are the potential difficulties of tolerating treatment postoperatively and the lack of an objective means to assess response after the primary tumor is removed. At least six randomized trials have evaluated the use of adjuvant chemotherapy following cystectomy for muscle-invasive TCC (Table 6.3) 59-63 . Although all of these trials used cis-platin-based chemotherapy and had surgery as a control arm, two trials primarily...

Hereditary vs Sporadic Breast Cancer Further Considerations

Although familial breast cancer tends to occur earlier than sporadic and differs histologically, the biology of the two diseases is similar. This observation might suggest that sporadic breast cancer involves random mutations in the same genes that control familial breast cancer. To date, this has not been observed. Statistically, an individual at higher risk of breast cancer due to a known genetic mutation would also be at risk for sporadic breast cancer due to random mutations at another genetic locus. DNA microarray analysis of hereditary and sporadic breast cancer cells may shed light on differences in the two entities. This information could be helpful in determining prognosis and designing therapeutic interventions.

Role of Diet in Preventing Breast Cancer

Most physicians today recommend well-balanced diets that are low in fat and calories and high in fiber, complex carbohydrates, fruits, and vegetables. These foods contain ingredients including antioxidants that may protect DNA from damage by absorbing and inactivating dangerous free radicals that are generated during normal metabolism. They also recommend physical exercise and weight management. Physicians may caution against excessive ingestion of alcohol since there is evidence that alcohol may increase breast cancer risk, especially in women who have no other risk factors. There is no question that physicians will recommend that their patients not smoke, and that they exercise regularly. These recommendations are for an overall healthy lifestyle, not just for prevention of breast cancer. The sale of these products, however, is driven by economics, not health. The likelihood of diet supplements and modifications in preventing breast cancer is probably small, and they will not cure a...

Can Breast Cancer Be Prevented

Although researchers and clinicians are continuing to learn more about the nature of genetic defects and environmental interactions that may lead to development of breast cancer, no magic bullet is currently available for prevention of the disease. In chapter 6 I discuss some of the state-of-the-art research relating to prevention and therapy for the disease. For example, studies have shown that women at high risk can benefit from prophylactic tamoxifen therapy, but there is increased risk of endometrial cancer and potentially fatal blood clots. For now, it will suffice to say that for women of average risk, there are probably no specific options for prevention other than leading an active, healthy lifestyle including exercise and a healthy, well-balanced diet. Some risk factors can be avoided, but involve conscious lifestyle choices. For example, a menopausal woman should carefully weigh the potential risks of classic HRT (breast cancer and cardiovascular disease) versus the benefits...

Current Treatments for Breast Cancer

If the lesion proves to be malignant, there is now a wide variety of treatment options. This book is intended to be a general guide, but new treatment protocols are constantly being developed. Different medical centers use different experimental and standard treatment protocols. Remember that every breast cancer is unique. The best option for a given patient is a matter for the patient and the health care provider. Today, patients are usually informed of their options and are given choices. Although it is important not to delay, they are usually given some time to think about the options and to arrive at decisions with which they and their loved ones are comfortable. In major medical centers, patients are often treated by a multidiscipli-nary team that may include a surgeon, radiation oncologist, medical oncologist, radiologist, pathologist, nurse practitioner, and social worker. Most traditional treatments for breast cancer involve some combination of surgery, chemotherapy, and or...

Chemotherapy for Testicular Cancer

The last 30 years have seen extraordinary advances in the management of metastatic germ cell cancer of the testis. Prior to the advent of cisplatin-containing chemotherapy in the mid-1970s, chemotherapy was highly toxic, and gave poor results, with cure unusual in those with advanced disease. Following the introduction of cisplatin, and subsequently etoposide, progress has been rapid, not least in the development of ancillary drugs (e.g., 5-hydroxytryptamine 5-HT3 antagonists and growth factors). Modern therapy is now usually curative, tolerable, and has few long-term side effects. Indeed, the current dearth of randomized trials for most subgroups of these patients is largely a testimony to the advances taking place during this period. In most modern studies, patients with semi-noma requiring chemotherapy (a minority group) are combined with those with nonsemi-noma. Patients with seminoma are a median of 10 years older than patients with nonseminoma, which may have important...

Treatment of Breast Cancer

Surgery is usually followed by an additional (adjuvant) therapy. A lumpectomy is usually followed by a course of radiation to destroy undetected cancer cells that may have been left behind in the breast, chest wall, or lymph nodes and that have the potential to metastasize. Some lumpectomy and most mastectomy patients also receive chemotherapy in which toxic drugs are given orally or by IV to block DNA synthesis or division of cancer cells (table 5.3). Although the drugs target tumor cells, they are not specific and affect all rapidly dividing cells such as those in hair follicles, intestinal lining, and bone marrow. That is why chemotherapy causes such unpleasant side effects as hair loss, vomiting, and low blood cell counts. Chemotherapy may also cause premature menopause and infertility. Chemotherapy is usually given in cycles, with each period of treatment followed by a period of recovery. The total course of treatment can span three to six months. Side effects usually vary with...

Postchemotherapy RPLND

After an intensive course of platinum-based chemotherapy for stage II to IV NSGCT of the testis, a residual mass will be apparent within the retroperitoneum on computed tomography (CT) or MRI scans (Fig. 21.2) in 25 or more cases 26 . It is now established practice to excise such residual masses in order to increase the chance of cure 27 . However, when the mass is < 1 cm in diameter, it most likely contains necrotic tissue only 28 and can be safely observed 29 . Patients with malignant teratoma intermediate that contains differentiated teratoma (MTI) are at risk of the tumor masses becoming cystic and enlarging during chemotherapy. Enlarging masses with falling tumor markers are characteristic of growing teratoma syndrome, which requires surgical removal of all tumor masses. All patients with MTI should have a CT scan after two or three courses of chemotherapy as masses in growing teratoma syndrome can become inoperable and there may be only a limited window of opportunity in which...

The Role of the Media in Breast Cancer Education

Increased advocacy for breast cancer funding has led to increased media coverage of the disease. In Denver, at least one local TV station is a major supporter of the annual Race for the Cure, and encourages a buddy-check system to remind women to do monthly self-exams. Feature stories of breast cancer patients, especially survivors, appear regularly on TV and in the newspapers. Unfortunately, the media is often motivated to report the news that sells the newspapers or increases ratings, and often sacrifices accuracy in the process. Reports of clinical studies often do not distinguish between those that are well controlled and those that are not. Observational studies may point to correlations between events or conditions, but do not determine cause and effect despite media reports to the contrary. Desperately ill patients and their families are given false hopes when the media convey promises of a new cure, only to retract the information several days later. The information is often...

Common Cancers Breast Cancer

A woman's lifetime risk of breast cancer is approximately 1 in 8. Breast cancer clusters in families the risk of breast cancer doubles for a woman with one affected first-degree relative (e.g., mother, sister, or daughter). The risk increases further if there are multiple affected relatives or if the relatives developed early-onset breast cancer. About 5 of breast cancer cases are inherited in autosomal dominant fashion, and most of these cases are the result of mutations in either the BRCA1 gene (chromosome 17) or the BRCA2 gene (chromosome 13). Women who inherit one of these mutations have an approximately 60 chance of developing a breast tumor. Women with a BRCA1 mutation also have at least a 20 chance of developing ovarian cancer. Both BRCA1 and BRCA2 are involved in the DNA repair process. Faulty DNA repair leads to an accumulation of harmful mutations in cells, ultimately causing a tumor to form. A small proportion of breast cancer cases are the result of mutations in the p53...

Node Positive Early Breast Cancer

Breast-conserving therapy with a wide excision (lumpectomy), axillary dissection (or sentinel node biopsy), and radiation therapy is considered the preferred treatment for most patients with stage I or II breast cancer. In patients at moderate or high risk of developing systemic metastasis, it is preferable to give adjuvant therapy, beginning with chemotherapy followed with radiation therapy. This patient has a high risk of recurrence because of the presence of lymph node metastasis, and it would be inappropriate to withhold further therapy. Another high risk factor that this patient has is that the tumor is larger than 1 cm. Recommended adjuvant treatment for patients with node-positive breast cancer is explained in the table below. A large number of prospective randomized trials, as well as recent overviews and meta-analysis of adjuvant systemic therapy, have determined that both chemotherapy and tamoxifen therapy reduce the odds of recurrence in breast cancer patients....

Expression of Specific Genes Associated with Breast Cancer Progression

Pieces (called oligomers) of DNA derived from cDNA sequences for known genes are embedded onto microchips and incubated with extracts from tumors. Tumor mRNAs hybridize with their cDNA counterparts and can be detected and identified. Since the cDNA sequences embedded on the chips are known, those that hybridize indicate which genes are being expressed in the tumor at that time. Microchips containing sequences of more than 30,000 genes are now commercially available. Tumor extracts can be assessed to determine which of all known genes are turned on and which turned off. The pattern reveals specific molecular pathways utilized by the cancer cells. These profiles give valuable information as to the biology of the tumor. Patterns may differ in different breast cancers and may help distinguish whether the cancer is sporadic or is due to BRCA1 or BRCA2 mutations. The profiles may also be useful in predicting how individual tumors might respond to different therapeutic interventions. To...

Biology of Sporadic vs Hereditary Breast Cancer

Recent studies have demonstrated that hereditary breast cancers often present different histological characteristics from those that occur sporadically. However, the biological behavior of tumors is often the same. In fact, younger women with hereditary breast cancer often do better than those whose tumors arise sporadically. Women who have two or more first degree relatives (mother, sister) with breast cancer have a greatly increased chance of developing the disease at a younger age, but the disease itself is not necessarily more aggressive. Overall mortality rates are similar between patients with hereditary breast cancer and those whose tumors arise spontaneously.

Breast Cancer Prognosis

A 65-year-old patient visits the gynecologist with a solid 2-cm mass in the upper outer corner of the left breast. A biopsy of the lesion is done, which is consistent with infiltrating ductal breast cancer. Epidemiology. Breast cancer continues to be the most common cancer diagnosed in women of western industrialized countries. An estimated 182,000 new cases of invasive breast cancer were expected to occur among women in the United States during 2000. After increasing by approximately 4 per year in the 1980s, breast cancer incidence rates in women have leveled off in the 1990s to approximately 110 cases per 100,000 women. Management. The preferred treatment for most patients with stage I or II breast cancer is considered to be breast-conserving therapy with a wide excision, axillary lymph node dissection or sentinel lymph node biopsy, and radiotherapy. Lymphatic mancipg and sentinel lymph node biopsy are new procedures that offer the ability to avoid axillary lvmph node dissection and...

Chemotherapy

Side effects of chemotherapy include loss of appetite, changes in taste and smell, mouth tenderness or sores, nausea, vomiting, changes in bowel habits, fatigue, leukopenia, and weight gain. Many side effects of chemotherapy dissipate quickly. Their frequency and severity depend on initial nutritional status, type and dosage of chemotherapy, and other drugs and treatments given simultaneously.

Biochemotherapy

The lack of cross-resistance, nonoverlapping toxicity, and potential synergy between chemotherapy and biological therapy has led to several trials combining cytokines and chemotherapeutic agents (so-called biochemotherapy) in metastatic renal cell carcinoma. One rationale for this approach is that by causing cyto-toxicity chemotherapy will release tumor antigens, which are processed by IFN-a-stimulated antigen-presenting cells that in turn activate IL-2-stimulated CTLs. The counterargument would be that chemotherapy may downregulate immunological responses. (PVI). Protracted venous infusion 5-FU- containing regimens have given high response rates in neoadjuvant treatment of breast cancer 66 and relapsed ovarian cancer 67 . Our study using IFN-a, IL-2, and 5-FU (PVI) showed an overall response rate of 31 in 55 patients (CR three patients PR 14 patients) 68 . Interestingly, there was a trend toward higher response rates and longer survival in the poorer prognosis group, although this...

Breast cancer

Breast cancer survivors are at increased risk for endometrial carcinoma. This maybe related in part to coexistent risk factors of obesity and higher circulating estrogen levels. Additionally, women who have been treated with tamoxifen for prevention of breast cancer recurrence experience an increased risk of endometrial hyperplasia and carcinoma related directly to the duration of tamoxifen therapy, with risk peaking for women taking tamoxifen as adjuvant therapy at two to five years of therapy in long-term population-based studies (odds ratio 5.1, 95 CI 2.1-13).15 The risk increases from four to nine times in women who use tamoxifen for longer than five years.16 Fewer data are available on other anti-breast-cancer drugs. Toremifene stimulates uterine tissues similarly to tamoxifen, whereas raloxifene has not been demonstrated to have any effect upon the endometrium in a randomized, double-blind trial.17

The Roles of Age Sex and Ethnicity

Although breast cancer can strike women in their twenties, it is primarily a disease of older age (table 1.2). At least 78 percent of patients are age fifty or older, and the incidence rate is increasing most rapidly in post-menopausal women. However, the incidence of breast cancer in women under age forty is also increasing. This is significant because the hormonal status of the female patient seems to play a role in the behavior of the disease. In younger women the tumors tend to be more aggressive, and the patients may have a less favorable prognosis. Table 1.1 Cumulative risk of developing sporadic breast cancer by age Risk of Developing Breast Cancer Pregnant or lactating (nursing) women are not immune from breast cancer. It is, in fact, the most common cancer among this group of women, occurring in approximately one per 3000 pregnancies in women ages thirty-two to thirty-eight. The diagnosis of breast cancer during pregnancy is often complicated by the need to avoid certain...

Interplay of Genetics and Environment

Inheritance of susceptibility accounts for only a small percentage of breast cancers. In order for a cell to become cancerous, changes must occur in the genetic information that regulates its growth and relationship to nearby cells. These changes are most likely initiated by environmental events. However, even though most people in a geographic area are exposed to the same environmental insults, only a fraction will develop breast cancer. In the majority of the population, the triggering of cancer may be pure chance. An older person accumulates more environmental insults and eventually may sustain enough critical events to trigger the disease. However, if one has inherited a susceptibility to develop cancer, the same environmental insults may trigger the disease process sooner. Thus, although the greatest risks for developing breast cancer are being female, aging, and inheriting predisposing genes, environmental factors appear to be critically important in initiating the disease...

An Introduction to Cancer Biology

In chapter 1, I introduced the concept of inherited versus sporadic breast cancer. In order to understand the role heredity plays in the development of the disease, it is important to understand what cancer is. Cancer is actually a catch-all term for many different diseases that share a fundamental defect a loss of regulation of cell division and differentiation. This loss is generally due to the alteration of certain regulatory genes known as oncogenes and tumor suppressor genes. Cancer may therefore be considered a genetic disorder, even if the genetic alterations involved are not inherited.

Derangements of the Cell Cycle and the Rise of Malignant Cells

Malignant cells that spread have acquired the ability to break free of their surroundings and invade blood and lymphatic vessels. This activity requires that the cells activate genes for enzymes that can break down the extracellular matrix that holds the cells in place in a tissue. Alternatively, changes may occur in the surrounding stroma to allow the altered cells to escape. This latter theory is currently the subject of experimental inquiry. If the cancer cells can successfully escape into the circulation and survive there, they may then travel to distant sites and invade other tissues and organs. This process of invasion and acquiring the ability to survive in a foreign environment is known as metastasis. Certain cancers have a pattern for metastasizing to specific sites that cannot be explained simply by the distribution of blood vessels and lymphatics that drain the tumors. For example, breast cancer often metastasizes to underarm lymph nodes and then to brain, lung, ovaries,...

The Nature of Breast Abnormalities Benign and Malignant Lesions

Breast cancers vary in biological behavior (for example, their growth rate) and tendency to metastasize. The least dangerous are those that arise in the lobule itself and do not spread. They are often found in both breasts (bilateral), but may never cause the patient any problems other than worry. This form of breast cancer is known as LCIS, or lobular carcinoma in situ. Some question whether they are true malignancies or markers of a potential Tumors that arise in the epithelium of the ducts can remain within the duct and are known as DCIS, or ductal carcinoma in situ. DCIS can acquire the ability to invade beyond the duct into the stroma. The most common breast cancer (80 percent of all breast cancers) is invasive ductal carcinoma. It may grow and invade locally, or it may travel through the lymphatics to other parts of the body. It is the danger of metastasis that makes this form of cancer such a concern. Other, less common breast cancers include medullary, colloid, tubular, and...

Special Genes Involved in Cancer Oncogenes and Tumor Suppressor Genes

Several tumor suppressor genes are associated with specific cancers including breast cancer. These include BRCA1, BRCA2 (breast cancer genes 1 and 2), and p53 (a protein product of a tumor suppressor gene). I will discuss these in greater detail in the following chapter. For now, it is sufficient to understand that these genes are part of the normal human genome and play a role in regulating cell division. If these genes are disrupted and do not function properly, the consequences may include the development of cancer. Some genes expressed by cancer cells prevent the induction of apoptosis, which would normally destroy a genetically damaged cell. An example of such a gene is BCL2. Some types of chemotherapy damage a cell's DNA and trigger cell death by apoptosis. A cancer cell expressing BCL2 is often resistant to apoptosis induced by chemotherapy. This is clearly a selective advantage to the cancer cell, but harmful to the patient.

Cancers Related to Specific Mutations eg Retinoblastoma Ataxia Telangiectasia

Some cancers are associated with specific gene mutations. I have already mentioned retinoblastoma, which occurs when the tumor suppressing the RB gene is lost or altered. Another disease, ataxia telangiectasia (AT), is caused by a recessive gene. AT patients have increased sensitivity to ionizing radiation and often develop leukemia or lymphoma. Their heterozygous relatives have an increased incidence of breast cancer. There are other cancers associated with inherited defects of specific genes, and some patients with these defective genes also have higher risks of developing breast cancer. These conditions are extremely rare.

Localization of BRCA1 and BRCA2

The hunt for the putative breast cancer genes in the 1980s and early 1990s was far more difficult given the limits of technology available at the time. For example, in the early 1980s, Mary-Claire King worked with a group of twenty-three breast-cancer families (i.e., families who had a number of individuals with breast cancer that were diagnosed before age forty-five). Seventeen showed evidence of genetic linkage to a specific marker on the long arm of chromosome 17, with a lod score of 5.98. This suggests that the likelihood of linkage to a predisposing cancer gene occurring by chance was nearly a million to one. (The other cancer families in this group did not show this linkage, suggesting that they either had a different gene that was responsible for their disease or were exposed to a common environmental agent that caused it.) And yet, the putative cancer gene was still ten cM from the marker, a distance that could encompass as many as five genes. There are many known mutations of...

Lowprevalence Risk Genes

In addition to p53 and AT, other genes may contribute to the development of breast cancer. Several low-prevalence risk genes are considered to be candidates for BRCA3, to account for the incidence of familial breast cancer not attributable to BRCA1 or BRCA2 mutations. These risk genes include rare alleles of common genes such as those regulating estrogen or androgen (male hormone) receptors. They also include rare alleles of genes coding for enzymes that are normally involved in detoxifying environmental carcinogens, such as cytochrome P-450, N-acetyl transferase, and gluathione-S-transferase. Abnormalities in these genes, which are normally expressed in breast tissue, may prevent normal detoxification of potentially dangerous substances, resulting in tumor initiation. It is increasingly apparent that breast cancer is a multifactorial disease, where the interplay of inherited susceptibilities and environmental factors determines who will ultimately develop the disease.

Modification of Genetic Risk Caused by Environmental Factors

The question arises whether a woman can modify her risk of breast cancer by altering environmental factors that may induce its development. This thinking can apply equally to those who have inherited a faulty gene or to those who are at average risk, since, in either case, environmental factors most likely provide the necessary genetic damage to initiate the onset of disease. Although female sex hormones are believed to increase the risk for breast cancer, the data is not completely clear. Overall, there appears to be some increased risk if a women begins to menstruate before age twelve, does not have children or has her first child after age thirty, does not breastfeed her children, or undergoes menopause after age fifty-five. The correlation appears to be with the number of ovulatory cycles the woman undergoes in her lifetime. The period between menarche and first pregnancy, during which time the breast tissue is developing, appears to be most sensitive to environmental insults,...

Genetic Testing for BRCA1 and BRCA2 Benefits and Consequences

A woman with a family history of breast cancer and or ovarian cancer may be facing more difficult questions. Tests are now available for the presence of mutated BRCA1 and BRCA2 genes, but there are many pros and cons to be weighed. There is no correct answer. What works for one woman may not work for another. The emotional consequences of testing are extremely difficult. Not every woman can handle the knowledge that she has a high probability of developing a potentially deadly disease at an early age. Once a woman learns that she is positive for BRCA1 or BRCA2 mutations, what does she do with that knowledge Although she is at much higher risk for disease, there is no guarantee that she will actually develop breast or ovarian cancer since the genes are not 100 percent penetrant. These women are still at risk for spontaneous breast cancer (although at a lower risk), as are women with family histories who test negative for the mutated genes. It is strongly suggested that women who...

Importance of Early Detection

Although the incidence of breast cancer is increasing, its death rate has been steady since 1990 and may even be dropping. Much of this increased survival can be attributed to increased awareness leading to early detection of the disease, and treating it before it has had a chance to spread. The importance of early detection cannot be stressed enough, whether or not a woman has a family history of the disease. Although there have been reports of new diagnostic tests, mammography remains the best screening technology available today. The newest mammography machines deliver minimal X-ray radiation and permit the trained radiologist to detect lesions as small as 0.5 centimeters (0.2 inches) (fig. 5.1). New digital imaging technology is further improving the detection of tiny lesions, especially in the presence of dense breast tissue. The American Cancer Society guidelines currently recommend that a baseline mammogram be done at forty years of age, then repeated every two years until age...

What Happens If You Find a Lump Diagnostic Procedures

Occasionally a man will discover a lump in his chest in the area of the nipple. He too should have a medical consultation, even though breast cancer in men is rare. If diagnosed late, it can be as deadly as in women. The risk in males is higher if they have a family history of BRCA2-associated disease. A male may also be referred for mammography.

Considerations for Alternative Medicine

Some patients choose to obtain care from practitioners of alternative medicine. They may consult naturopaths, homeopaths, or herbologists, and are treated with assorted diets and herbal therapies. None of these, however, has ever been tested on breast cancer in a clinical trial, nor is there any credible evidence of their effectiveness. Furthermore, some unproven treatments can interfere with standard medical treatments or may cause serious side effects. Nevertheless, alternative medicine is becoming so popular in the United States that some medical schools are beginning to discuss its use as adjuncts to evidence-based treatments. Co-treatments by practitioners of alternative medicine may offer some comfort to patients who are

Potentials for Gene Therapy

The protocols for treating breast cancer do not differ between patients with hereditary or spontaneous disease, since the diseases are not different. Much attention has been placed on Human Genome Project discoveries and the possibilities of gene therapy. Patients with known BRCA1 or BRCA2 mutations wonder whether these defective genes can be corrected by such treatment. While gene therapy is perceived as a treatment of the future, current experience is a mixed bag. It is especially difficult to address issues of germ-line mutations (which BRCA mutations are) given the current controversy and restrictions on embryonic stem cell or fetal tissue research. I address this issue in greater detail in chapter 6.

The Need for Emotional Support

Physicians and others who care for breast cancer patients are becoming more sensitive to quality-of-life issues. An important part of breast cancer therapy is emotional support both for the patient and for the family. Many women feel a deep sense of loss following mastectomy and even lumpectomy, and need the support that can be provided by professional counselors. Chemotherapy often causes hair loss, induces premature menopause, and may cause serious mood swings that affect not only the patient but also her loved ones. Many medical centers now provide integrated services including physicians, surgeons, nutritionists, and social workers as part of a team. Patients often have supportive family members and friends, or may be part of a religious group or other organization that provides support sessions and religious healing services. A diagnosis of cancer is a life-altering event even if the prognosis for long-term survival is excellent.

The Search for More Predisposing Genes

The discovery of BRCA1 and BRCA2 has launched a new era in the quest to understand the causes of breast cancer. Now that the human genome has been mapped, the focus of molecular biologists will be on understanding the role of the approximately 35,000 genes that define a human being. A new field of proteomics is being developed in which the role of gene-encoded proteins is studied. Already, the dogma that one gene encodes a single protein is not certain. The gene encodes the primary backbone of the protein, but other factors control the processing that makes the three-dimensional, functional molecule and regulates how the molecule functions in the cell. There are many questions concerning genetic intervention in multifactorial diseases such as breast cancer. We already know that BRCA1 and BRCA2 do not account for all the cases of hereditary breast cancer, and that the disease is influenced by other genes and environmental factors. It is likely that, in coming years, other predisposing...

The Role of Crosstalk Between Malignant Cells and Their Surroundings

A focus of current research is to understand how a malignant cell's environment modifies its behavior. This approach is called epi-genetic, because the target is not the gene itself but rather factors that regulate the expression of the gene. A gene may be damaged, but its expression may be controlled so that its altered product may not be produced. In other words, cancer may be preventable if we can change the environment the gene acts on rather than changing the genetically altered cell. For example, researchers have focused on the role of genetic damage in the ductal cells in initiating breast cancer, but the role of the surrounding stromal cells has been more or less ignored. It is now increasingly apparent that there is crosstalk between the ductal cells, where breast cancer usually begins, and surrounding cells, and that the stroma may play a role in preventing carcinoma in situ from breaking through into an invasive cancer. It has also been postulated that specialized...

Focus on Prevention and Control If Not Cure

As mentioned earlier, a major current focus of breast cancer research is on prevention and control. Understanding the complex interaction of susceptibility genes and environmental stimuli including dietary factors may lead to drugs and even vaccines that may help prevent the disease in high-risk people. Further understanding of the role of epigenetic interactions, may enable control of the disease, even if a cure is not feasible.

Role of Environment

Epidemiologists have noted that Japanese women, who normally have a low risk for developing breast cancer, eventually acquire the same risk as other Americans if they move to the United States. This observation and others suggest a role for environmental factors in the development of the disease. Scientists have studied the effects of exposure to many environmental and dietary factors that might contribute to the increasing incidence of breast cancer in Western countries. They have examined the effects of dietary fat, air and water pollutants, pesticides, radiation, alcohol, stress, oral contraceptives, hormone replacement therapy, and even abortions. They have also studied the effects of chemicals known as xenoestrogens, environmental chemicals that behave like estrogens. Organochlorines, for example, are common pollutants that exhibit estrogenic activity. These chemicals include PCBs, organic components of industrial waste that may leak into the water table. To date, none of the...

Risk Factors

While the link between environment and breast cancer remains unclear, a number of factors that increase the risk of developing the disease have been identified. The most important risk factor is age (table 1.1). A woman younger than fifty years, with no other risk factors, has only a 2 percent risk of developing the disease. In contrast, if she lives beyond eighty-five years, her risk is 12.5 percent. Other major risk factors include the age of menarche (first menstrual period), parity (number of pregnancies), whether she breast-fed her children, and age at menopause. These factors suggest a strong role for hormones, especially estrogens, in developing breast cancer. Use of hormone replacement therapy (HRT) over many years also increases risk, as may obesity and heavy ingestion of alcohol. Women who inherit susceptibility to breast cancer (altered BRCA1 and BRCA2 genes, chapter 4) have a greater probability of developing the disease at a younger age. Their risk of contracting breast...

Understanding Risk

Many women find breast cancer statistics frightening. They often see the one in eight statistic in women's magazines and assume they will inevitably get breast cancer. It is no longer considered a matter of if but rather when. Almost everyone knows someone who has been struck by the disease. Ashkenazi Jewish women fear that they have inherited the dreaded breast cancer genes and wonder if they will pass it on to their offspring. Women who know they carry a mutated form of BRCA1 or BRCA2 wrestle with how to prevent what they deem is an inevitable outcome. I have explained earlier that although the incidence of breast cancer is rising, the statistic one in eight reflects a cumulative or additive risk throughout an individual's lifetime. This type of risk is calculated across the general population, without taking into account ethnic or genetic differences or specific environmental factors that may alter the risk, and is called an absolute risk. Absolute risk is expressed as the number...

Chemoprevention

Recent five-year clinical trials of the anti-estrogen compound tamoxifen indicated that chemoprevention may be an effective method of preventing breast cancer in high-risk individuals (including lobular carcinoma in situ, and those with mutated BRCA1 or BRCA2 genes). However, as I indicated above, tamoxifen is not without its own risk. It may lead to endometrial hyperplasia or cancer or cause thromboses. It also causes temporary premature menopause, with all the associated discomforts, and some patients develop resistance to the drug. New studies are under way comparing tamoxifen to a similar drug, raloxifene (Evista ), that may have similar beneficial effects with fewer side effects.

Diagnostics

Diagnostic imaging techniques are intended to identify tumors at the earliest possible stages. Ultimately, the goal is to distinguish between dense tissue, benign lumps, and cancer. To date, mammo-grams still offer the best imaging available for early diagnosis of breast cancer. However, they are not foolproof, and miss perhaps 10 percent of cancers. In younger women with dense breast tissue, mammograms may not distinguish a small tumor from surrounding tissue, although digital enhancing may enhance the sensitivity. They often cannot detect lobular carcinoma in situ in early stages. They are not reliable in women who have breast implants, nor do they distinguish fluid-filled cysts from solid fibroadenomas as well as does ultrasound. Current research is focused on better imaging with the least possible radiation.

Therapeutics

Cancer therapy, including that for breast cancer, has traditionally taken a slash, poison, and burn, approach where the tumor is subjected to surgical eradication, followed by chemotherapy and radiation to remove any malignant cells that may remain. Although this aggressive approach is still used, efforts are made to use the most conservative surgery possible (including options for breast reconstruction where possible), chemotherapy protocols based on increased knowledge of the biology of the disease, and radiation that targets the tumor but as little normal tissue as possible. Chemotherapy for cancer generally employs chemicals that poison all rapidly growing cells. New knowledge of the molecular and genetic bases for cancer is enabling the development of drugs that target cancer cells more specifically, thereby eliminating some of the side effects. An example of molecular based therapy is Herceptin, the new antibody against the Her2 neu receptor. Her2 neu is expressed in 70 percent...

Gene Therapy

Elucidation of the genes involved in breast cancer is prompting continued research in gene therapy. The goal of gene therapy is to replace the defective gene with a normal one or to counteract its expression, and thereby prevent the inherited disease from occurring. Other gene therapy approaches target cancer cells with a lethal gene that will kill just the malignant cells but not normal surrounding cells. There have been some success stories with this approach in conditions caused by single gene defect. There have also been failures, including a well-publicized case in which a young man died during experimental gene therapy that was not clinically necessary. Many of the problems of gene therapy involve the delivery of the target genes to the site in which they must act. The gene is carried in a vector that must seek out only the correct target. This is especially difficult to achieve in a heterogeneous, metastatic cancer. A recent study targeted elements in the stroma of a tumor...

Political Issues

Biomedical research is expensive, and is subject to political posturing as advocates lobby for funds for their pet diseases. Although efforts to secure funds for breast cancer research are now extremely visible, it is only in recent years that the disease entered national consciousness. As recently as forty years ago, breast cancer was considered a shameful disease, one that was kept in the closet. Patients who had suspected breast tumors signed consents for breast surgery. If the biopsy proved to be positive, they were treated immediately with disfiguring radical mastectomies. They did not learn if they still had a breast or if they had cancer until they awoke from the anesthetic. They generally had little emotional support from their physicians or even from their families. The American Cancer Society initiated the Reach to Recovery program in 1952, in which breast cancer survivors would visit newly diagnosed (and treated) patients and reassure them that there really is life after a...

Hope for the Future

Breast cancer remains a serious illness in the early twenty-first century, but like many diseases of earlier eras it is slowly revealing its molecular secrets. The mapping of the human genome is paving the way for extensive research as to how genes work, how they are regulated, and what their protein products do in normal cells and in disease. Discoveries will lead to the development of better drugs and new methods of treatment that may ultimately prevent the disease. The cloning of BRCA1 and BRCA2 in the past decade was a major breakthrough, but it was just a beginning in the molecular battle against breast cancer. While researchers have learned that defects in these genes (and in other cell-cycle regulators) often lead to breast and or ovarian cancer, it has not been easy to extrapolate this knowledge to cases of sporadic breast cancer. Although we know that genetic damage is necessary for cancer to occur, BRCA1 and BRCA2 are not usually the site of damage in sporadic cases. The...

National Programs

Advocacy for breast cancer information and to prevent genetics-based insurance discrimination. Living Beyond Breast Cancer A Philadelphia-based organization whose mission is to empower all women affected by breast cancer to live as long as possible with the best quality of life. National Alliance of Breast Cancer Organizations (NABCO) Membership organization providing information about breast cancer. National Breast Cancer Coalition 1707 L Street, NW Suite 1060 Coalition of cancer patients focused on changing public policy as it relates to progress against breast cancer. A network of major cancer research and treatment institutions including City of Hope National Medical Center, Dana-Farber Cancer Institute, Fox Chase Cancer Center, Fred Hutchinson Cancer Research Center, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Huntsman Cancer Institute at the University of Utah, James Cancer Hospital and Solove Research Institute at the Ohio State...

Penetration of the Epithelial Barriers

Immunosuppression and altered mucosal integrity (mucositis) due to chemotherapy or malnutrition (e.g., Candida spp. and anaerobic and other enteric bacteria in the bowel). Some microbes do not invade tissues at all and affect the host locally and systemically by liberating toxins at the site of colonization (e.g., diphtheria exotoxin).40

Inherited Genetic Changes

Tive risk of prostate cancer in BRCA1 carriers was 2.95 compared with the general population. A later study from the Breast Cancer Linkage Consortium also found that in breast ovarian cancer families with a deleterious BRCA2 mutation, the relative risk for prostate cancer was 4.65 13 . Furthermore, this risk was even higher before age 65. Subsequent analysis of 38 prostate cancer familial clusters found no germline mutations in BRCA1 however, two novel deletions were found in BRAC2 14 . The authors of this report proposed that BRAC2 germline mutations might account for up to 5 of prostate cancers in familial clusters.

Rxr Functional Activities

The first application of rexinoids in clinical studies took advantage of their efficacy in triggering apoptosis, in contrast to cell differentiation seen with retinoids (Mehta et al., 1996 Nagy et al., 1995). This led to their successful use since the 1980s in the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Presently, a number of cancer types and cell types are being tested for their possible responsiveness to rexinoids, such as acute myeloid leukemia (Altucci et al., 2005), aerodigestive tract cancer (Dragnev et al., 2005), human breast cancer cells (Toma et al., 1998), or pancreatic cancer cells (Balasubramanian et al., 2004). Along the same line, chemopreventive n-3 fatty acids in colon were shown to activate RXR in colonocytes (Fan et al., 2003).

Concurrent Malignancy

DVT is more common in patients with a malignant tumour, an observation made for the first time by Trousseau 47 in 1865. DVT can be the first sign of cancer and is taken as a warning sign for malignant disease. The thrombogenic effect of cancer arises from the production of humoral factors (procoagulants), mechanical factors (vein compression or local infiltration) and general factors indicated by the presence and increased levels of acute phase reactants 5 . Indirectly, thrombosis may also be induced by reduced patient mobility and diminished uptake of vitamins such as folates. Finally, thrombosis may be promoted by the treatment received by the patient including radiotherapy and chemotherapy 31, 49 , and may also be triggered by postsurgery fibrosis.

Dietary factors that may increase risk

Alcohol has been associated with cancer of the mouth, pharynx, larynx, breast, esophagus, cervix, and liver. Women should limit intake of alcohol to no more than one drink per day (360 ml beer, 150 ml wine, 30 ml 100-proof spirits). Women who are at high risk for breast cancer may consider not drinking any alcohol. The combination of alcohol and tobacco use increases risk far more than either one alone.

Evidence for the Genetic Etiology of Prostate Cancer

So far, genotyping data have been reported in over 1600 families. There are numerous conflicting reports supporting or refuting linkage within many areas in the genome. This challenges our understanding of the genetic basis of this disease. This search is distinct from the search for a familial breast cancer predisposition gene, in which analysis of linkage in select regions revealed a site where the BRCA1 gene was situated 14 . This work shows that the

Impaired Wound Healing

Malnutrition has long been observed to profoundly influence wound healing at multiple points in the phases of wound repair. Protein malnutrition or vitamin C deficiency directly inhibits collagen synthesis and deposition, leading to a retardation of the healing process (2-5). Patients with malignancies frequently have impaired nutrient intake and potentially tumor-induced altered substrate utilization. Various antitumor treatments such as chemotherapy and radiation

Candidate Gene Analysis Evidence BRCA2 NBS and CHEK2 Genes

The candidate gene approach is used to search for genetic markers of disease susceptibility, where a gene is targeted based on the characteristics of its protein product. PCa cases were noted, in the early 1990s, to be clustered within breast cancer families 52,53 . The RR of PCa in male carriers of mutations in the breast cancer predisposition genes BRCA1 and BRCA2 is increased. The RR with respect to BRCA1 was found to be 3.33 54 and 1.82 in a further study by the Breast Cancer Linkage Consortium (BCLC) 55 .

Necrotizing Enterocolitis

Me was diagnosed as neutropenic (due to aggressive cytotoxic chemotherapy) a few days ago. Neutropenic enterocolitis is a fulminant form of necrotizing enteritis that occurs in neutropenic patients neutropenia is often related to cyclic neutropenia, leukemia, aplastic anemia, or chemotherapy. In postmortem exams of patients who have died of leukemia, infections of the cecal area ( TYPHLITIS) are frequently found C. septicum is the most common organism isolated from the blood of such patients.

Pathways To Cancer From Replication Defects

Expression of the Rad21 cohesin is downregulated in certain tumors 83 . In addition, HP 1 is downregulated in breast cancer cells that are metastatic or invasive 89 . The S. pombe homolog of HP1, Swi6, recruits Rad21 to centromeres and other regions of heterochromatin 14, 144 . Recently, phosphorylation of another cohesin subunit, Smc1, has been shown to be required for the S-phase checkpoint in human cells 87, 207 . Taken together, these connections suggest a direct role for chromatin structure in maintenance of genome stability.

Cancer Treatment and Research

Gradishar, WJ., Wood, W.C. (eds) Advances in Breast Cancer Management. 2000. ISBN 0-7923-7890-3. Sparano, Joseph A. (ed.) HIV & HTLV-I Associated Malignancies. 2001. ISBN 0-7923-7220-4. Ettinger, David S. (ed.) Thoracic Oncology. 2001. ISBN 0-7923-7248-4. Bergan, Raymond C. (ed.) Cancer Chemoprevention. 2001. ISBN 0-7923-7259-X. Raza, A., Mundle, S.D. (eds) Myelodysplastic Syndromes & Secondary Acute Myelogenous Leukemia 2001. ISBN 0-7923-7396. ISBN 0-7923-7523-8. Stack, M.S., Fishman, D.A. (eds) Ovarian Cancer. 2001. ISBN 0-7923-7530-0. Bashey, A., Ball, E.D. (eds) Non-Myeloablative Allogeneic Transplantation. 2002. ISBN 0-7923-7646-3. Leong, Stanley P.L. (ed.) Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer. 2002. ISBN 1-4020-7013-6. Andersson , B., Murray D. (eds) Clinically Relevant Resistance in Cancer Chemotherapy. 2002. ISBN 1-4020-7200-7.

What Do Men with Prostate Cancer Think of Screening for the Disease

Public perception of screening for the disease varies. There is widespread pressure for the establishment of national screening programs, with resistance to this pressure often misinterpreted as attempts to save money, deceive the public, or even as sex discrimination. A recent interesting and elegant qualitative research study by Chapple et al. 35 highlighted these feelings, interviewing 52 men with prostate cancer from various geographical areas of the U.K. Although some factual conceptions were revealed, there were also many misconceptions, such as early diagnosis brings better chances of cure, 5-year survival figures in the U.S. are higher than in Britain because of PSA screening programs, PSA testing is not taking place because of lack of resources in the NHS, men should be tested for prostate cancer as women are for breast cancer, men with urinary tract symptoms should all be tested for prostate cancer, and the government is not spending enough money on prostate cancer...

Oral Contraceptive Side Effects

Against primary and secondary osteoporosis (due to hypogonadism, glucocorticoid excess, immobilization, hyperthyroidism, diabetes mellitus, or primary hyperparathyroidism). Estrogen supplementation is the first choice for prevention and treatment of osteoporosis in women who are postmenopausal. The mechanism of action is thought to be decreasing bone resorption by inhibiting the synthesis of interleukins such as IL-6 as well as retarding the bone-resorbing effects of PTH. Estrogen is contraindicated in pregnancy, breast cancer, or active hepatitis. Side effects include breast tenderness, migraines, and vaginal bleeding spotting. Long-term adverse effects include gallstones, breast cancer, and thrombophlebitis. Estrogen alone also increases the risk of endometrial cancer, and progesterone is often added to decrease this risk.

Intermittent Hormonal Therapy

Among the most important quality of life issues for patients with prostate cancer is the loss of sexual function with treatment. For this reason many men delay treatment or take treatment intermittently. There is no evidence whatsoever that intermittent treatment is less successful than continuous therapy. Indeed, if one examines the effects of hormonal treatment on prostate cancer cells growing in culture, then a single exposure to antiandrogen therapy is seen to cause devastating destruction of cell cultures rather akin to the effects of chemotherapy.

The Cancer Connection

Most cancer cells are partially compromised in their ability to respond to DNA damage or replication blocks, which limits the effectiveness of current cancer treatments that involve the use of DNA-damaging agents such as chemotherapy and radiation. Therefore, manipulation of these pathways may allow us to design more effective therapeutic regimes for the treatment of cancer. For example, cells could be rendered more sensitive to genotoxic agents by inactivation of an additional branch or signaling point of the checkpoint pathway. Our studies with the yeast pathways regulated by Rad53 Dun1 and Chk1 have shown that indeed this is the case. Such treatments would render cancer cells more sensitive to chemotherapy or radiation treatment. Several investigators are using both S. cerevisiae and S. pombe to test this hypothesis by using the yeasts as genetic tools to inactivate interactions among different players in the response to DNA damage.

The Treatment of Recurrent Prostate Cancer

Platelet-derived growth factor receptor (PDGFR) positivity is reported in 10 to 70 of patients' biopsy specimens. For this reason, inhibitors of PDGFR action have been investigated in prostate cancer. Agents inhibiting PDGFR may do so through a number of routes, varying from direct blockade of the receptor itself to inhibition of downstream effector mechanisms. There is no evidence to date that these agents have activity in prostate cancer, though there has been interest recently in the combination of such agents with cytotoxic chemotherapy, and in one such study docetaxel in combination with imatinib has been shown to be of interest 9 .

Studies in Seventh Day Adventists

These studies are reviewed below. However, as early as 1958, Wynder and Lemon examined cancer and heart disease in SDA hospital patients compared with non-SDA patients.18 In this early study, based on 564 SDA and 8128 non-SDA patients admitted to eight SDA hospitals throughout the U.S., lower risk of epidermoid lung, mouth, esophagus, larynx, and bladder cancer were found in the SDAs than in the non-SDAs. Colon and rectum cancer, however, were not found less frequently in the SDA than the non-SDA comparison group, while prostate and breast cancer were found somewhat more frequently in the SDA patient series. Interviews with study subjects indicated that only 41 of the SDA patients consumed any meat, whereas 95 of the general population consumed meat. A further follow-up of this population was completed through 1976 and Standardized Mortality Ratios were reported comparing age-adjusted mortality rates in California SDAs to the U.S. white...

Hormonal fluctuations

Beginning in the mid thirties, more than one-third of American women undergo total abdominal hysterectomy with bilateral oopherectomy (TAH BSO). Hysterectomy is the second most common surgical procedure in women in the USA after cesarean section, with more than 600 000 occurring yearly.24 Ovarian blood supply is reduced post-hysterectomy, leading to earlier menopause (approximately four years earlier) for women who have undergone hysterectomy without oopherectomy when compared with physiologic menopause.25 Women who have undergone TAH BSO or chemical menopause via chemotherapy may experience more intense menopausal symptoms given the more abrupt change compared with natural menopause.26 Pharmacotherapy or herbal therapy might assist the women through symptomatic menopause and enhance sexual desire. Hormonal supplementation, often with added androgens, can offset perimenopausal symptoms and enhance sexual interest.

The Side Effects of Hormonal Therapy

As time has progressed, the GnRH agonists have also been shown to have side effects. These include memory loss, parkin-sonism, anemia, and osteoporosis, in addition to the hot flushes and impotence that were obvious from their first use. The most important of the side effects physiologically is osteoporosis, with a loss of bone mass of nearly 10 per annum. Although bispho-sphonates have been shown to be of little effect in prostate cancer in terms of limiting pain and tumor progression, which are the main benefits of their use in breast cancer and myeloma, this group of agents is of significant use in limiting osteoporosis in prostate cancer 11 .

New Adventist Health Study

*Adjusted for age at entry, age at first pregnancy, age at menarche, menopausal status, history of benign breast disease, maternal history of breast cancer, education and weight. As with the analysis of fatal breast cancer, no strong relationship between consumption of animal products and breast cancer risk emerged from the new incidence study. After controlling for the effects of several covariates known to be associated with breast cancer risk (e.g., age at first menstrual period, age at first full-term pregnancy, and body weight), risks associated with meat intake were negligible. Comparing current use of meat, poultry and fish in those who consumed these products more than three times per week with never users, a non-significant relative risk of 1.33 was found, thus indicating that meat was only weakly associated with breast cancer in this study, if at all.29

Analysis Interpretation

Of the 145 SMRs or relative risks that were less than 100, 39 were deemed to be statistically significant (i.e., not due to chance). These figures varied when evaluating specific cancer sites, however. For colon cancer, out of a total of 20 studies, 19 (95 ) reported an SMR RR less than 100 (or 1.0). Six of these were statistically significant. For the other cancer sites evaluated, this figure was lower. For prostate cancer, only 55 of the SMRs reviewed were < 100 (none significantly so) while for breast cancer 67 were < 100, of which one was significantly less than 100 and two were significantly greater than 100. Table 4.3 summarizes the percent of SMRs and or RRs less than the null value for all cancer sites combined as well as for colon, prostate, breast, lung, stomach, pancreas and ovarian cancer as well as for the lymphatic hematopoietic cancers. When within-group comparisons are evaluated where dietary variation exists (e.g., within the SDA populations), several patterns...

Hormone Refractory Prostate Cancer

Hormone-refractory prostate cancer is defined as disease that progresses despite castrate testosterone levels, and is refractory to all hormonal manipulations including withdrawal of antian-drogen therapy. Until recently, there had been no standard chemotherapeutic approach for HRPC. Several agents had been evaluated in clinical trials, but many older studies suffered from methodological deficits such as small numbers of patients, heterogeneity of enrolled patients, and lack uniform response criteria 5 . Overall there have been very few recent phase III trials completed in HRPC (Table 4.1) making it difficult to draw firm conclusions about the efficacy of many regimens. However, it would appear that chemotherapy at a minimum does provide a palliative benefit. Non-chemotherapy-based approaches to palliation also exist. External beam radiotherapy, for example, remains the mainstay of treatment for patients with bone pain, spinal cord compression, or painful urinary obstructive symptoms....

Soy Isoflavones and Breast or Prostate Cancer Risk

Several case-control studies and one cohort study have reported on the relationship between soy intake (or indirect measures of intake) and breast cancer risk. These studies are summarized in Table 4.4. In a study in Singapore involving 200 breast cancer cases, breast cancer risk was reduced approximately 60 among women in the highest quintile of soy consumption, compared with those in the lowest quintile of soy consump-tion.39 However, this relationship was observed only in premenopausal women. In a larger hospital-based study in Japan, those women consuming soy three or more times per week had approximately 20 lower risk of Table 4.4 Summary of Epidemiologic Studies of Soy Tofu Intake and Breast Cancer Risk Table 4.4 Summary of Epidemiologic Studies of Soy Tofu Intake and Breast Cancer Risk breast cancer than those women who consumed soy less frequently. Again, the findings of a protective relationship were restricted to premenopausal women only.40 Two studies in China (one in...

Dietary Fiber and Cancer Risk

There are few studies on the relationship between dietary fiber intake and cancer risk for cancers other than colon rectum. Studies on breast cancer show mixed results for fiber,56-58 but a more consistent, protective role for fiber appears evident in regard to pancreas cancer.59

Mitoxantrone and Prednisone

A Canadian study led by Tannock et al. 17 randomized 161 symptomatic patients with HRPC to receive either mitoxantrone every 3 weeks with daily prednisone or prednisone alone. The primary end point of this study was palliative response, which was defined as a significant improvement in either pain or analgesic usage or both (neither could get worse). In the mitox-antrone arm, a statistically significant improvement in pain relief (29 vs. 12 , p .01) and a prolonged duration of this palliative response (43 weeks vs. 18 weeks, p < .0001) was demonstrated. These patients also reported improvements in physical and social functioning, global quality of life, anorexia, drowsiness, constipation, and other symptoms 18 . The use of mitoxantrone was also associated with a higher PSA response rate and time to progression. There was no survival benefit of chemotherapy, although a crossover to mitoxantrone in patients who progressed on prednisone was allowed and may have impacted on the survival...

Nuclear transport receptors

70-90 of tumor cells in a population of invasive ductal and lobular breast carcinomas 6 . The functional yeast homologue of CAS is a protein called Cselp, which was originally isolated in a screen for yeast mutants with defects in chromosome segregation 113 . It is possible that CAS Cselp serves as a critical regulator of growth control that when altered can cause uncontrolled cell growth or cancer. It seems likely that other transport receptors may also be implicated in tumorigenesis in the future. Consistent with this notion, a recent study identified a translocation of a novel human karyopherin, RanBP17, in acute lymphoblastic leukemia 39 . In addition, a truncated form of the NLS receptor, importin a, has been identified in the human breast cancer cell line, ZR-75-1 59 .

Whole Grains and Cancer

There is a wide range of protective substances found in whole grains that exert their effect through various mechanisms including antioxidant activity, hormonal effects, binding of carcinogens, and otherwise influencing the environment of the gut in a beneficial fashion.60 A recent review of some 40 case-control studies (involving 20 different types of cancer) found a pooled odds ratio of 0.66 (99 confidence interval 0.60-0.72) for high vs. low whole grain intake.61 Most odds ratios in this review were < 1 for studies of colorectal cancers (or polyps), other gastrointestinal cancers, all hormone-related cancers, and all studies of pancreas cancer. Most of the odds ratios for the various cancer sites that were reviewed were of the order of 0.5 to 0.8, although for both breast and prostate cancer the relationship was not as pronounced. The odds ratios for breast cancer studies was 0.86 and was even higher for the prostate cancer studies reviewed (odds ratio 0.90). Overall, there...

Maturation Of Immune Responses And Antimicrobial Immunity

Although it was speculated for some time that there might be a subset of regulatory T cells (TR), it was not until these cells could be identified by cell surface markers that definitive studies could be performed. In both mice and humans, the major population of TR is CD25+, CD4+. CD25 is the a-chain of the high affinity IL-2 receptor. TR have rearranged T cell receptors and are antigen specific many of them react with host antigens. Once activated, the TR secretes IL-10 and TGF-0 and suppresses the immune response nonspecifically. The importance of TR has been shown in mice and humans. Mice that are depleted of CD25+, CD4+ lymphocytes rapidly develop autoimmune disease and in humans genetic deficiency of Foxp3 transcription factor, which is downstream of CD25 signaling, is associated with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome).55 In normal subjects, lymphocytes reacting with self-antigens with high affinity are eliminated in the thymus....

Estramustine TaxaneBased Therapy

By combining mitoxantrone, docetaxel, and low-dose pred-nisone in a phase II multicenter trial, Freeman 33 showed a PSA response rate of 69 and a trend toward improvement in quality of life end points after two cycles of chemotherapy. This is another regimen that will be investigated further.

Alternative Explanations for Low Cancer Risk in Vegetarians

Data have suggested that colon cancer may be associated with cigarette smoking (but only after a long latency period).64-65 The more relevant question today may be which cancer sites are not associated with tobacco the list appears to be quite short and currently includes prostate, endometrium, and breast cancer.

Recent Recommendations on Vitamins and Chronic Disease Prevention

American Cancer Society (177) Antioxidants are substances that protect the body's cells from damage caused by free radicals (byproducts of the body's normal processes). Examples of antioxidants include vitamin C, vitamin E, -carotene, and selenium. If you want to take in more antioxidants, health experts recommend eating a variety of fruits and vegetables, which are good sources of antioxidants. Taking large doses of antioxidant supplements is usually not recommended while undergoing chemotherapy and radiation therapy. Talk with your doctor to determine the best time to take antioxidant supplements.

Medical consequences of longterm alcoholism Harmful effects

Many studies report that moderate to heavy alcohol consumption increases the risk for breast cancer.35 A meta-analysis involving more than 150 000 women with and without breast cancer showed an increased relative risk of breast cancer of 1.32 (95 CI 1.19-1.45) for an intake of 35-44 g of alcohol per day. The relative risk increased by 7.1 for each additional 10 g day alcohol-intake.36 The investigators concluded that if the observed relationship is causal, then about 4 of the breast cancers in developed countries are alcohol-related. A prospective cohort study of approximately 45 000 postmenopausal women has shown that the relative risk is doubled when alcohol consumption is combined with hormone replacement therapy.37 In contrast, smoking has little or no independent effect on the risk of developing breast cancer.36

Beneficial effects of alcohol consumption

Before the age of 60, breast cancer is a more important cause of death than heart disease. Later on, the risk of heart disease exceeds that of breast cancer, so the benefits of moderate drinking are more apparent. The consumption of at least one drink a day by mid-life and elderly women is associated with a 20 reduction in the risk of cardiovascular disease compared with non-drinkers.38 Like men, women appear to experience a U-shaped relationship between alcohol consumption and coronary artery disease.

Genetic Characterization

Few as 1 leukemic cell in 104-106 normal cells and therefore is very useful for the detection of MRD after cytoreductive therapy. A problem is the risk of false-positive results owing to contamination of reagents. New opportunities are emerging with the development of quantitative PCR. With techniques called real-time PCR, quantification of PCR products is more easily and more accurately reached than before, allowing one to determine the kinetics of leukemic cells during and after chemotherapy.

Combinations of Targeted and Cytotoxic Therapy

Targeted therapy in combination with chemotherapy is another area of active research. Several trials have assessed the combination of targeted therapies such as thalidomide, calcitriol, and exisulind with docetaxel. Thalidomide glutarimide is a synthetic glutamic acid derivative that was initially used for morning sickness but was taken off the market due to teratogenicity and neuropathies. Thalidomide has antiangiogenesis effects, inhibits cytokines including tumor necrosis factor-a, and can alter cell adhesion molecules. In a randomized phase II trial with 75 HRPC patients, comparing thalidomide and docetaxel with docetaxel alone,Leonard et al 55 reported a PSA response rate of 50 ,and an increase in median survival by 14 months. Gastrointestinal, neurological, and thromboembolic toxicities were reported, the latter necessitating the use of prophylactic anticoagulation. Larger trials incorporating palliative end points, and more data on toxicity are needed to determine whether this...

MMR and Separate Vaccines

Common side effects of the MMR include a sore arm for 1-2 days. Most effects, however, .occur 1-2 weeks after immunization. These include signs or symptoms of the components of the vaccine. Measles can cause a rash, fever, or upper respiratory infection symptoms. Mumps can cause slight salivary gland swelling. Rubella may present with cervical lymph adenopathies and arthralgia. The MMR vaccine can present with all of the above. All the vaccines can cause febrile seizures and a reversible encephalopathy. The MMR should be delayed for pregnancy or possibility of pregnancy in the patient, for anything more than a minor illness, and if the patient has received gammaglobulin in the past 3 months. Contraindications include anaphylaxis to any of its components or immunodeficiency such as cancer, leukemia, severe HIV immunosuppression, radiation therapy, chemotherapy, and steroids. There is no proof that MMR vaccination causes autism.

Relative Risk of Clinical Prognostic Factors

The factors that predict the biological potential of superficial lesions must be correctly weighted before deciding on cysto-scopic surveillance protocols and adjuvant therapy. The relative importance of the prognostic factors was measured by multi-variate analyses of two Medical Research Council (MRC) trials 26 and two EORTC-GU trials 20 . In the MRC analyses, tumor number at presentation and tumor recurrence at the first follow-up cystoscopy at 3 months were statistically better at predicting recurrence than all other prognostic factors. The confidence of these observations compared with the (subjective) interpretation of other histopathological data led Hall et al. 27 to propose a cystoscopic and adjuvant chemotherapy protocol based on these two factors alone. In the EORTC-GU analyses, the relative risk of disease progression was assessed 20 . The greatest risk was in those with frequent disease recurrence, followed by tumor grade and size. Surprisingly, the T stage at presentation...

Geographical Distribution

Leprosy occurs throughout the world but predominates in tropical and subtropical regions. The problem is greatest in Central Africa and Southeast Asia. Worldwide there are about 5.5 million cases of leprosy, but it is estimated that the total number of cases is actually 11.5 million of which 4 million are in India. In the Americas there are 400,000 cases of which 70 are in Brazil with a prevalence of 1.7 per 1000 inhabitants. The Unites States has more than 7,000 cases, most of them from immigrants. According to WHO the prevalence of leprosy has been modified because the patients that have undergone a course of chemotherapy are not considered active. For the first time the number of reported cases has declined from 5.37 million in 1985 to 3.1 million in 1992. In Mexico, of 16,694 reported cases in 1989 there were only 6,106 active patients, and 7,946 were successfully treated. This gives a prevalence rate of 0.6 per 10,000 inhabitants.

Role of Transurethral Resection TUR and Tumor Surveillance Recurrence and New Occurrence

It was previously assumed that the incidence of recurrence is low following cystoscopic extirpation of tumor, and that most treatment failure is a result of new occurrences in remote areas of de novo urothelial dysplasia. It is now apparent that as many as 50 of recurrences are due to tumor reimplantation at the time of original resection, as evidenced by molecular studies that demonstrate that many synchronous and metachronous lesions are of similar clonal origin 33,34 . Early tumor recurrences, which are multifocal and orientated toward the bladder dome (which occur in less than 5 of first presentations), are more likely to be as a result of the mechanical dispersion of freed tumor cells during resection (which gravitate upward) rather than genuine new occurrences. Later recurrences are more likely to be of disparate clonal derivation and represent genuine new occurrences. It is interesting to note that it is only the incidence of early tumor recurrence that is reduced by...

Incompetent Terminal Patients Right To Refuse Upheld In One Case Overridden In Another

Salkewicz (Mass. 1977), the court authorized the withholding of chemotherapy for 67-year old Joseph Salkewicz, a profoundly retarded man. It was felt that he would not have understood the pain resulting from chemotherapy, and would have had to be held down physically for doctors to give him the necessary drugs and blood transfusions. The court summed up its decision as follows. To presume that the incompetent person must always be subjected to what many rational and intelligent persons may decline is to downgrade the status of the incompetent person by placing a lesser value on his intrinsic human worth and vitality, it is of interest to note that, like John Storar, Salkewicz was a mentally retarded person who had never been competent. Yet, in the Storar case (held 4 years later in New York) the court did not allow the terminally ill and incompetent Storar patient to refuse blood transfusions. Observes medical ethicist Ruth Macklin Cases that are...

Intravesical Immunotherapy and Recurrence Progression Rates

Intravesical immunotherapy using BCG was first proposed by Morales et al. 49 in 1976. Conventional prophylactic regimes of 6 weekly instillations, similar to those used for chemotherapy, resulted in complete response rates of 60 to 100 at 1 year, 55 to 75 after 2 years, and mean recurrence-free intervals of 10 to 22.5 months 50 . Although the long-term response rates with BCG are less enduring, the reduction in recurrence appears to be better than the rates achieved using most chemotherapy agents. This superiority is supported by comparative studies of BCG and anthracycline agents, which suggest that BCG has a roughly twofold advantage over Adriamycin and epirubicin (with an overall BCG tumor recurrence rate reduction of approximately 30 ) 51 . In contrast, trials comparing MMC directly with BCG have been less consistent in outcome, and passionately debated. Of the published comparative MMC-BCG studies, three have suggested that MMC may have therapeutic equivalence to BCG for patients...

Intravesical Therapy and Dose Scheduling

The traditional induction regimen of six weekly instillations of chemotherapy,initiated a week after resection, was based on original work using BCG immunotherapy. Delayed bladder instillation was intended as a prophylactic therapy for a secondary new occurrence, presuming that all previous tumors have been eradicated. It is now increasingly apparent that intravesical chemotherapy is best intended as an ablative therapy to mop up loose cells released at the time of extirpation and to prevent tumor reimplantation. Longitudinal studies have shown that tumor recurrences occur in two time-dependent peaks. The groups with early recurrence peaks are sensitive to chemotherapy, whereas those with delayed recurrences are generally resistant 35 . It is not surprising, therefore, that the influential study of the MRC demonstrated that immediate instillation of MMC within 24 hours of transurethral resection was as effective as conventional 6-week courses 61 . Indeed, more recent studies have...

Insertion of Central Catheters

The technique of internal jugular and subclavian vein catheterization is indispensable to the clinician. The placement of central venous catheters is necessary for the administration of parenteral nutrition, long term antibiotics, central pressure monitoring, vasopressor therapy, chemotherapy and, in some circumstances, large volume resuscitation. The placement of these catheters is not without risk, and several investigators have studied the role of ultrasound guidance in decreasing this risk. This chapter will summarize the literature on the use of ultrasound as an aid to central venous cannulation and attempt to come to a conclusion on the role of this technology.

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