Introduction
Cancer breast is the one cancer among women which produces the largest casualties.
There are several ways to watch for it and notice the earliest symptoms of this fatal illness. Detecting it early is the best way to deal with it. It is an illness which affects ladies in
hundred thousands while comparatively only a handful of men are affected. Genetic predisposition is another factor related to Cancer Breast. Being so, ladies who have a predisposition can be detected early through genetic tests. Tests ad follow-up are expensive. Insurance companies do not help for genetic testing. They may cut on insurance money for people with a predilection for any cancer. Employers may discriminate when giving jobs. The essay deals with various opinions across political, social, medical and journalist circles. I have highlighted a few articles including research and newspaper reports of the political issues involved.
Genetic Predisposition to Breast Cancer
Breast cancer is the most prevalent malignancy in females. Though the numbers of new cases are increasing, the mortality is decreasing for various reasons. As in all cancers, many risk factors are assigned to breast cancer too. Genetic predisposition is only among the many.
Incidence in women is so high that the issue cannot be neglected. There are 205000 new cases every year by the SEER estimate and 180000 by the NCI estimate.
(Breast Cancer, Adviware Pty Ltd). Only about 1000 men are involved. Incidence rate is 1 in 1326 or 0.08% people in the USA. This calculates to around 23 new cases per hour. Undiagnosed prevalence comes to about 1 million or 0.37% or 1 in 272 people. Australia estimates that 1 in 11 women would have breast cancer positively (Breast Cancer, Adviware Pty Ltd). Mari Suzuki, Professor Doug Brutlag in an article dated May 19, 2005 has pointed out that cancer breast numbers are increasing due to “better detection tools, new statistical methods, longer life spans and changing lifestyles of American women”. Their choice to have their first baby later in life and hormonal treatment for symptoms of menopause further increase the risk of breast cancer in women.
DNA (deoxyribonucleic acid) is the chemical that make up our genes. Genes provide instructions which decide how cells behave in division. They control how our cells grow, divide and die (American Cancer Society, 2007). Some genes cause rapid cell division and are known as oncogenes. There are others which slow down cell division or cause cells to die at the right time and are called tumor suppressor genes. Cancers are caused by mutation changes in the DNA when they turn on the oncogenes or turn off the tumor suppressor cells. Some genes are found responsible for breast cancers in families (American Cancer Society, 2007). Normally BRCA genes would protect against cancer as indicated by Mari Suzuki, Professor Doug Brutlag, in her article “Breast Cancer and Genetic Testing” dated 19/5/2005. However their mutations BRCA1 and BRCA2 are tumor suppressor genes inherited from one’s parents. Families with knowledge of existence of these genes are forewarned about the possibility of developing breast cancer (American Cancer Society, 2007). They then take steps to be alert all through their life and monitor changes in their breasts in order to discover a problem as early as possible so that the cancer is still in a treatable stage. Acquired mutations resulting in the oncogenic and tumor suppressing genes are also possible. These could occur due to radiation or cancer causing chemicals. Tests to identify acquired mutations are not very accurate (American Cancer Society, 2007).
In a CME discussion at the 7th International Conference on Adjuvant Therapy in Primary Breast Cancer it was reported that the 2 predisposition genes, high penetrance breast cancer susceptibility genes, BRCA1 and BRCA2, have been implicated in 40% of hereditary breast cancers. 35 to 70% of women who appear to have predispositions to breast cancer probably have genes which have not been identified yet. The breast cancer risk ranges from 50% to 85% in different groups of people. Prophylactic mastectomy has been said to reduce the chances of developing genetically caused breast cancer by 90%. Benefits of hormone intervention are doubtful by the discussion at the Seventh International Conference (Pritchard et al, Medscape).
Moreover in BRCA1 carriers, the breast cancers were estrogen receptor negative and thereby not hormone dependent. Prophylactic oophorectomy (hormonal therapy) is reported to reduce development of cancer breast in ladies with genetic predilection but not many studies have substantiated this (Pritchard et al, Medscape). One study suggests that tamoxifen reduces cancer breast risk in the same group. However a study in England refuted this finding. So hormone therapy cannot be considered a form of treatment. Considering that the BRCA1 type of genetic breast cancer is the more prevalent of the 2 kinds, tamoxifen or any hormonal therapy may be redundant. When the effect of the drug Raloxifene was studied on osteoporotic women, the effect it had on breast cancer was obtained as a secondary outcome. Some inference that it is useful as a prophylactic has been made. Another suggestion has been that LHRH agonists in combination with raloxifene or other agents may prove useful for chemoprevention (Pritchard et al, Medscape).
King et al studied the effect of tamoxifen on the incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project between April 1, 1992, and September 30, 1999 was done (King at al, 2001). Of the 288 cases, 19 inherited disease predisposing BRCA1 and BRCA2 mutations. Of 8 patients with BRCA1, 5 were given tamoxifen and 3 placebos. Of 11 patients with BRCA2, 3 received tamoxifen and 8 placebos. Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial (King at al, 2001). In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Further investigation still needs to be done to see if tamoxifen should be started at a younger age (King at al, 2001).
Vidarsdottir et al studied breast cancer risk associated with AURKA 91T → a polymorphism in relation to BRCA mutations. 759 breast cancer patients, including 9 BRCA1 and 98 BRCA2 mutation carriers, and 653 mutation-negative unaffected controls were genotyped for the AURKA 91T. Individuals homozygous for the 91A allele were found to be at increased risk of breast cancer compared to 91T homozygote. Cases carrying BRCA mutations were excluded to make results more correct. Results showed that BRCA cases differed from sporadic cases and their allele distribution was similar to controls. A statistically significant increased risk of sporadic breast cancer for individuals that are homozygous for the 91A allele with no effect in carriers of BRCA mutations was the result.
Glaser et al (2004) reviewed the studies on the herpes virus, Epstein Barr virus in association with breast cancer. The difficulty in these studies was the isolation of the virus from the tumor cells. This virus was first noticed in 1995 in 21% of breast tumors (Glaser, 2004). It is understood that the virus is transmitted through saliva and primary infection occurs in the oral mucosa. The virus is a 184 DNA Genome which encodes approximately 100 genes and replicates by producing new virions. Even after control of infection by immune responses, latent infection persists (Glaser, 2004). Periodic lytic infections in the oral mucosa results in the shedding of virions increasing the possibility of passing it onto others. EBV has been linked to several cancers like African Burkitt’s Lymphoma, Hodgkin, AIDS, and nasal NK/T-cell lymphomas, post-transplant lymphoproliferative disorder; nasopharyngeal carcinoma (NPC); lymphoepithelioma-like squamous cell malignancies; gastric adenocarcinoma and leiomyosarcoma (Glaser, 2004). EBV was classified as a group 1 carcinogen.
Glaser discusses the various techniques available for isolation of the virus: PCR (highly sensitive method), Southern Blot Hybridisation, In situ Hybridisation, Immunohistochemistry, Laser capture microdissection studies and multiple analytic methods. Virus has been found most consistently and in highest prevalence (10-15 %) using the PCR method. Some studies have found that EBV positive breast cancers are more aggressive. It is more suitable to interpret that there is no association of EBV with breast cancer in the context of limitations (Glaser, 2004). Recent technologic advances now make it feasible to better tackle the methodological challenges of detecting EBV in breast cancers. A recent National Cancer Institute recommendation specifies an approach combining real-time quantitative PCR, which allows measurement of the amount of viral DNA in archival tissue samples, with laser capture microdissection to improve localization of viral DNA to benign or malignant components of a tissue sample (Glaser, 2004). Present public health and clinical considerations justify that appropriate laboratory research strategies must be used on appropriate selection of cases of appropriate sizes, include subsets of patients likely to be at risk for an EBV-associated tumor based on prior studies of EBV in breast and other cancers (Glaser, 2004)
Kriege at al conducted a research study into the usefulness of Magnetic Resonance Imaging screening for breast cancer in women with familial or genetic predisposition (2001). The aims of this study were to investigate: the value of regular surveillance in women with a familial or genetic predisposition for breast cancer, the efficacy of MRI as compared to mammography, cost-effectiveness of regular screening and quality of life during surveillance. 2500 women were studied. The usefulness of MRI over mammography was proved.
Cancer genetics is greatly integrated into oncological care especially in breast cancer. The recognition of breast cancer predisposition syndromes like BRCA is important in that there is a risk of other cancers too apart from breast cancer and a higher risk of contralateral breast cancer (Turnbull, 2005). Radiation is to be avoided in patients with genetic predisposition to breast cancer. However there is still a controversy on this issue. Radiation in radiosensitive types of genetic cancers is also avoided if genetic type of breast cancer accompanies alongwith. (Turnbull, 2005).
According to researchers at Brooke Army Medical Center, San Antonio, Texas, patients with low-expressing HER2 tumors exhibited better response, not only immunologically, but clinically, with decreased breast cancer recurrence and no mortality following vaccination with HER2 peptide E75 vaccine. It offers the hope of additional adjuvant therapy to the largest subset of breast cancer patients if proven in the upcoming phase III trial. According to them clinical trials with the HER2 E75-peptide vaccine in lymph node–positive and lymph node–negative patients with breast cancer who demonstrated varying levels of HER2 expression. Of 163 patients assessed, 92 underwent vaccination. 29 (34 percent) were defined as HER2 over-expressors, and 56 (66 percent) were defined as low-expressors.
The 71 patients in the control group included 22 (33 percent) over-expressors and 44 (67 percent) low-expressors, immunologic responses were similar as measured by delayed-type hypersensitivity reaction in the vaccination arm ; however, patients who were low-expressors of HER2 demonstrated an increased number of E75-specific CD8+ T cells when compared with the vaccinated over-expressors. After 30 months , disease recurrence rate were same in the vaccinated groups and the control groups. In fact, recurrence was very much reduced for vaccinated patients with low HER2 expression. The mortality rate among the vaccinated low expressors was zero. These findings may be significant for more than 50 percent of breast cancer patients whose tumors come under the HER2 low-expressing category. This research was presented at the American Association for Cancer Research 2008 Annual Meeting, April 12-16.
At this point of time, let us not forget the discovery of a hoax where the HPV for cancer cervix is concerned. For years the whole world was advocating the HPV vaccine for cancer cervix. An article by FDA tells the story. “The FDA news release of March 31, 2003 acknowledges that “most infections (by HPV) are short-lived and not associated with cervical cancer”, in recognition of the advances in medical science and technology since 1988. In other words, since 2003 the scientific staff of the FDA no longer considers HPV infection to be a high-risk disease when writing educational materials for the general public whereas the regulatory arm of the agency is still bound by the old classification scheme that had placed HPV test as a test to stratify risk for cervical cancer in regulating the industry.” (FDA, 2003). Though the Human Papilloma Virus is one cause of cancer cervix and the incidence of HPV is high, it is an infection which subsides very fast. The FDA has known this fact since 2003. Caution must be practiced before we play with our fellow human beings’ lives. Let us not make them scapegoats but for a few dollars.
Rothenburg (1999) in an article “Social Implications of Genetic Testing’ discusses the predictive implications of genetic testing and its impact on the insurance companies. While she agrees that the Human Genome Project has the potential to improve the health of the nation, it would be highlighting genetic differences across individuals and ethnic groups (Rothenburg, 1999). If the Human Genome Project is to be successful, the public fears of discrimination in insurance and employment must be allayed. The article analyses the State and Federal Legislation on genetic privacy and discrimination. She speaks of the possible harm that could arise out of widespread genetic testing. Her claim that if everything could be reduced to a person’s genes, genetic reductionism or genetic myopia, a person’s normal health behavior could be affected. Genetic testing should not be used as a quick fix and help the insurance people (Rothenburg,1999).
The evolution of genetic testing legislation began in the states in the 1970s and 1980s. Initially the states limited the freedom of the insurance companies and allowed them to assess risk without forcing the individuals to undergo any predictive tests or even reveal the results of such tests (Rothenburg,1999). The Federal Government passed the Health Insurance Portability and Accountability Act of 1996 which provided specific language about genetic information (Rothenburg, 1999). It specifically stated that genetic information cannot have an impact on insurance eligibility or continuing eligibility. Secondly as a social message, it stated that in the absence of a diagnosis related to a condition, it must be assumed that there is no such pre-existing condition (Rothenburg, 1999). If a healthy insured woman underwent a predictive diagnostic test for breast cancer and found herself positive following which she developed the cancer, her insurance coverage or benefits should not be limited. She must be considered healthy when she bought her insurance. The medical establishment has said they feel uncomfortable about not putting genetic information in medical records because of patients’ fears that the information may be used against them (Rothenburg, 1999).
Despite heavy marketing, genetic tests are still not widely done. Tests are done for people with family history of breast cancer. Kenneth Offit, Chief of the Clinical Genetics Service at the Memorial Sloan-Kettering Cancer Centre, says that patients at risk are then subjected to Magnetic Resonance Imaging every year to rule out breast cancer from age 25. (Mathews, Wall Street Journal). The mammograms on the other hand are done from age 35. Ladies who have taken oral pills as contraception have to be advised to be careful of breast cancer. Legislation is expected to be passed to stop insurance companies and employers from showing discrimination against those found positive for the genetic tests. Many new tests are yet to be accepted by the medical personnel (Mathews, Wall Street Journal). Tests are often costly. The Genetics test for the BRCA test sometimes is covered by the Federal Medicare Programme for patients who meet certain criteria.
Jesse Holland has reported in the Association Press that the anti-genetic discrimination bill has been passed in the House in Washington on the first of May, 2008. Companies would no longer be able to use genetic information to make insurance or job decisions against clients at risk for “cancers, heart disease or other ailments” (House approves bill prohibiting genetic discrimination, International Herald Tribune). Lawmakers and advocates have described this as “the first major civil rights act of the 21st century” (House approves bill prohibiting genetic discrimination, International Herald Tribune). Mr. George Bush is expected to sign this Genetic Information Nondiscrimination Act soon. Discrimination in rejecting job applications, promotions or health care coverage or in setting premiums will be dealt with through this Act.
Conclusion
Genetic predisposition to breast cancer is an established fact. Of many genes possibly implicated, the BRCA1 and the BRCA2 are the most common. Genetic testing is costly. Once the predisposition is established , frequent investigations like self examination, mammography and MRI may be done. The chances of detecting the earliest stage or onset of the cancer is greater now. Chemotherapy scares off most ladies. Hormone therapy and the use of tamoxifen as prophylactic treatment have not been established. BRAC2 seems to be amenable to prevention by Tamoxifen. Prevention and being forwarned by genetic tests are a safe manner of facing the situation. Experiments galore are going on. The lastest is the possibility of a preventive vaccine.
Mr Bush, the President of the United States, will sign soon to implement the Genetic Information Non Discrimination Act which would protect patients from the insurance hawks and employment agencies. Much research has to go into the final introduction of a preventive vaccine for Cancer of the Breast. The privacy of the ladies is to be protected. The breast cancer being the commonest cancer needs to be researched deeply and widely to finally come up with a plausible solution.
References
“Breast Cancer,” Adviware Pty Ltd, 9/4/08, 3/5/08, Adviware Pty Ltd. Web.
“Breast Cancer Prognosis: Response To Preventive HER2/neu Peptide (E75) Vaccine Based On HER2/neu Status”, 13/4/08, 3/5/08, Web.
“Do We Know What Causes Breast Cancer?”, 13/9/2007, 3/5/08, Web.
American Cancer Society. Glaser, Sally L.; “Epstein-Barr Virus and Breast Cancer: State of the Evidence for Viral.
Carcinogenesis”, Cancer Epidemiology Biomarkers and Prevention, Vol 13, Pgs. 688-697, 2004, American Association for Cancer Research.
Food and Drug Administration, 2003, Web.
“House approves bill prohibiting genetic discrimination, 1/5/08, 3/5/08 , International Herald Tribune, Web.
King et al, “Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.” JAMA. 2001;286(18):2251-6. Web.
Kriege, M.; “MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study”, Journal of Familial Cancer, Springer Netherlands Vol 1.3-4 2001.
Mathews, Anna Wilde; “Which genetic tests are really worth getting’, 1/5/08, Wall Street Journal, Academic Press Limited. Web.
Pritchard, Kathleen I.; “Genetic Predisposition and Chemoprevention”, Medscape. Web.
Rothenburg, Karen L., “Social Implications of Genetic Testing” North American Actuarial Journal, Vol 3, No. 1 , Pgs, 133-136.
Suzuli, Mari; “Breast Cancer and Genetic Testing”, 19/5/2005, 3/5/08,.
Turnbull et al, “Radiotherapy and Genetic Predisposition to Breast Cancer “, 2005, ElsevierB.V. Web.
Vidarsdottir, Linda et al, “Breast cancer risk associated with AURKA 91T → A polymorphism in relation to BRCA mutations”, Cancer letters, Vol 250 Issue 2, 8/6/07, Pgs 206-212 , ScienceDirect, Published by Elsevier Ltd.