Genetic testing of breast cancer: The widening horizon

This story is of a beautiful girl who has almost everything it takes to make life complete and fulfilling. She is a successful career woman. She has a loving family. She is a doting mother to her kids. She is physically fit and is blessed with good health. But fate wanted to throw an unpleasant surprise at her when she underwent a medical examination, a gene sequencing test. The results of her BRCA1 and BRCA2 gene testing projected an exponentially high risk of developing breast cancer in the near future. This was further complicated by her discouraging family history of breast tumours. Her scenario changed dramatically. She was scared of the impending doom.

However, a ray of hope ushered in when she learned that preventive measures can be exercised. But, the choice was tough. She was told that the only panacea to avert her risk of breast cancer was prophylactic surgical removal of the breasts, also known as mastectomy. This presented a huge personal dilemma to her. She had to choose between her own physical appearance and her health, future and family. The benefits certainly outweighed the drawbacks of the procedure; she thought of it pragmatically, futuristically and like a modern woman before she opted to go under the surgeon’s knife for excision of her breasts. She is none other than the one and only heart-throb of millions and millions of fans across the globe, Angelina Jolie.

Angelina’s story speaks volumes about the phenomenal impact of the advancements in medical diagnostics; on the lives of people, all over the world.

“Nevertheless, it is ironical that though tremendous progress has been made in the realm of breast cancer diagnostics; direct benefits of these diagnostic advancements have touched the lives of very few women, particularly in developing nations like India,” said Dr BR Das, President, Research and Innovation, SRL. “It is time that we made an effort to reach out to all women with a family history of breast cancer and at least spoke about the availability of such a test,” he added.

Breast cancer epidemiology: Emerging trends

Epidemiological data presented in the 2006-2008 report of the Population Based Cancer Registry (PBCR) which is a subset of the National Cancer Registry Program, reveals a dismal picture1. The report shows that almost half of India’s breast cancer cases are below the age of 50 years. The analysis revealed that breast cancer comprised 22 per cent to 32 per cent of all female cancer cases in major Indian cities with the most alarming incidence reported in Mumbai. Globally, breast cancer accounted for 23 per cent (1.38 million) of the total new cancer cases and 14 per cent (458,400) of the total cancer deaths in 2008. About half the breast cancer cases and 60 per cent of related deaths are estimated to occur in economically developing countries like India2. As per recent data published by the WHO, the five-year survival rate of moderately advanced breast cancer cases in India was 48 per cent3. This is notably low as compared to the robust 89 per cent five-year survival rate in the US, as revealed by the American Society of Clinical Oncology (ASCO) in 20094. These figures compel us to introspect on the low five-year survival rates of Indian breast cancer patients in comparison to their Western counterparts. The answer lies in the degree of robustness of ‘breast cancer awareness campaigns and routine diagnostic surveillance.’

The Western world has succeeded in reducing the burden of this disease and in escalating survival rates; primarily due to stringent and meticulous large scale routine screening of breast cancer and huge mass awareness campaigns. This diligent effort seems lacking in the Indian healthcare system. Negligence in routine screening leads to breast cancer being undiagnosed in its initial stages. As a result, most patients are diagnosed only when the aggressive metastatic Stage 3 or 4 cancers develop. In fact, what makes us really uneasy and apprehensive is the PBCR report’s finding that the most aggressive forms of breast cancer, (HER2 positive, ER/PR negative or the worst variety HER2/ER/ PR negative) are much more rampant among the young age group in India1.

Low incidence but high mortality: Indian irony

With respect to breast cancer incidence and mortality figures; a comparison of India with other countries of the world, elucidates some interesting facts. The reported incidence of breast cancer is much higher in countries like the US and UK than that in India (101 in the US and 87 in the UK versus 19.1 in India per 100000 women)5. This is primarily because most cases of breast cancer are diagnosed during routine screening, documented and reported while calculating incidence rates, in the Western world. The converse is true for India. Due to relatively less stringent community surveillance of breast cancer, innumerable Indian cases remain undiagnosed and thereby unreported. These cases are missed out while accounting for Indian incidence rates and are identified only when progressive symptomatic disease strikes. Thus, though the incidence rates are lower, India’s breast cancer mortality figures are ironically higher than the western world. The overall percentage of breast cancer deaths at India stood at about 50 per cent a decade ago while similar mortality figures for China and the US were a meagre 30 per cent and 18 per cent respectively5.

The ‘Diagnostic Mix’ with a special focus on BRCA1/BRCA2 testing

To alleviate the burgeoning burden of breast cancer cases, the Indian healthcare system should exercise potent measures to ensure regular screening, early diagnosis and risk forecasting for breast cancer. Hence, a ‘diagnostic mix’ of routine mammograms and clinical examinations; along with gene testing for high risk candidates (testing for BRCA1 and BRCA2 mutations) seems the most pragmatic solution. Within this diagnostic mix, BRCA1 and BRCA2 gene testing for high risk group of women offers clinical advantages which are very distinct from those of routine mammography and clinical examination. BRCA1 and BRCA2 gene testing provides the benefit of forecasting the genetic tendency of a healthy individual to develop breast cancer in the future; an advantage not available through other surveillance methods6.

Identifying the right candidates for BRCA1 and BRCA2 gene testing

A detailed family and personal history can prove very instrumental in deciding whether a woman is a suitable candidate for BRCA1 and BRCA2 testing. Women with a pronounced family history of breast cancer involving first and second degree relatives, a familial history of ovarian cancer, a family history positive for BRCA1 and BRCA2 mutations or BRCA1 and BRCA2 positive tumours seem to be ideal candidates for BRCA1 and BRCA2 gene testing6. Besides these, certain known high risk subgroups, like women with a history of late pregnancies, those with early menarche and late menopause, those with a history of past long term hormone replacement therapy (HRT) or currently ongoing HRT, obese women with a physically inactive lifestyle and those with a history of chronic or regular alcohol consumption; can also be considered for BRCA1 and BRCA2 testing5. In case of these high risk subgroups, clinician’s judgement on a case-to-case basis and individual patient choices would drive the decision to undergo the gene test.

BRCA1/BRCA2 mutation positive cases: Prophylactic and preventive measures

Women for whom the BRCA1 and BRCA2 test reveals a positive result, several precautionary and prophylactic measures can be exercised. In cases wherein the percentage of risk projected by the BRCA1 and BRCA2 test is too high, prophylactic mastectomy can be resorted to, after thorough oncological consultation. This procedure involves bilateral surgical removal of the breast tissue. As much of the ‘at-risk’ breast tissue as is possible is removed during this procedure. This minimises the possibility of developing breast cancer in the future to very negligible levels. Presently, there are no clear cut universally accepted clinical guidelines or recommendation criteria to judge the eligibility of a woman to undergo prophylactic mastectomy based upon BRCA1 and BRCA2 test results. Therefore, decisions to opt for prophylactic mastectomy post BRCA1 and BRCA2 testing are purely made upon a case-to-case basis6.

Risk-mitigation plans would typically involve prophylactic control of factors that are known triggers of breast cancer. This would include a precautionary regimen comprising of reduction of obesity, avoidance of alcohol, indulgence in strenuous physical activity, avoiding the use of hormone replacement therapy, avoiding late pregnancies, breast feeding, using birth control pills for contraception and opting for oophorectomy in consultation with a qualified medical specialist, if needed.6,7 These changes can help women with BRCA1 and BRCA2 mutations to significantly reduce the risk of developing breast cancer. One could counter argue that most of these generic lifestyle changes can be recommended to any woman as a safeguard against breast cancer, regardless of BRCA1 and BRCA2 status. However, for BRCA1 and BRCA2 mutation positive high-risk women, these lifestyle changes are not just recommended but are almost mandatory and warranted.

Chemoprophylaxis is yet another potent weapon in the armoury of breast cancer risk reduction. Clinical studies have shown that administering anti-cancer agents like tamoxifen and raloxifene to high risk subgroups of women can significantly reduce the risk of developing breast cancer or its recurrence. These agents have been approved by the US FDA for chemoprevention of breast cancer in known high risk subgroups5.

Cancer genetic testing: A peek into the future

A market research report by RNCOS revealed that the global genetic testing market which stood at $1.5 billion in 2010 is expected to touch the $4 billion mark by 2015.8 According to this report, the oncology segment will predominate the realm of genetic testing worldwide.

However, the realm of genetic testing is faced with multiple ethical concerns. The bioethics of genetic testing revolves around issues like the social stigma attached to an abnormal genetic status, the panic created by abnormal gene test results, the financial and personal implications of gene test results on the lives of patients, the need for precise and sensitive genetic counselling and deciding the therapeutic options to be chosen based on gene test results. These are a few examples of the ethical issues involved which can not be ignored. There are umpteen other ethical dilemmas associated with genetic testing, beyond the scope of this write up, which need to be addressed prior to and after testing. Besides, affordability of genetic testing remains a major concern especially in a country like India; though the costs of several gene tests have now reduced dramatically, making them more affordable to patients. However, in spite of the ethical dilemmas and other obstacles, genetic testing is considered as a promising diagnostic tool. The clinical utility of genetic testing continues to captivate the attention of patients and the healthcare fraternity worldwide.

References:

1. Consolidated report of the Population Based Cancer Registry (PBCR) report (2006-2008). Accessed at http://www.breastcancerindia.net/bc/statistics/trends.htm on 1st June 2013
2. Jamal, B. Freddie, M Melissa, Jacques F, E Ward and Forman D; GLOBOCAN 2008. Global cancer statistics. Ca Cancer J Clin 2011;61:69–90
3. Cancer Survival in Africa, Asia, the Caribbean and Central America. WHO’s IARC publication number 162. IARC-SurvCan, Lyon 2011
4. American Society of Clinical Oncology data accessed on 1st June 2013 at http://www.breastcancerindia.net/bc/statistics/stati.htm
5. J. Fertay, F. Bray et al; GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, IARC Cancer Base No. 5, Version 2.0; IARC Press, Lyon 2004
6. National Cancer Institute fact sheet on ‘BRCA1 and BRCA2: Cancer Risk and Genetic Testing’. Accessed at http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA on 1st June 2013
7. Rebbeck T, Levin A, Eisen A, Snyder C, Watson P, Cannon-Albright L et al. Breast cancer risk after bilateral prophylactic oophorectomy in brca1 mutation carriers. JNCI J Natl Cancer Inst (1999) 91 (17): 1475-1479
8. RNCOS. Global genetic testing market analysis. Accessed at http://www.rncos.com/Report/IM352.htm