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What we think we know about the BRCA (Breast Cancer Susceptibility Associated) genes causing cancer is patently false, according to a new meta-analysis on the extant literature on the subject of these gene variations on breast cancer survival prognosis.
A groundbreaking new meta-analysis published in PLoS titled,"Worse Breast Cancer Prognosis of BRCA1/BRCA2 Mutation Carriers: What's the Evidence? A Systematic Review with Meta-Analysis", calls into question the value of using BRCA1/2 gene status to determine breast cancer survival prognosis, as is common practice today. This implications of this research may have wide-ranging effects as the present climate, following Angelina Jolie's high profile decision to have prophylactic breast, ovary and fallopian tube removed due to her perceived "genetic inheritance," is to equate BRCA status with bona fide and mathematically calculable disease risk certainty.
Jolie's decision to subject herself to multiple prophylactic organ removal was based on the premise that her BRCA mutations would result in an 87 percent lifetime risk of developing breast cancer and up to 54 percent chance of ovarian cancer, as prognosticated by her doctors. The notion that BRCA genes have full or near full penetrance (the ability of a mutation to cause clinically identifiable disease) has profound implications for the health of millions of women who rely on these predictions to make life and death medical decisions.
Because of a wide range of conflicting conclusions on the subject of BRCA's role in determining cancer risk and prognosis, researchers in the new study attempted a systematic and quantitative synthesis of evidence using the following method:
"Eligible publications were observational studies assessing the survival of breast cancer patients carrying a BRCA1/2 mutation compared to non-carriers or the general breast cancer population. We performed meta-analyses and best-evidence syntheses for survival outcomes taking into account study quality assessed by selection bias, misclassification bias and confounding."
They summarized their findings:
"Our review shows that, in contrast to currently held beliefs of many oncologists and despite 66 published studies, it is not yet possible to draw evidence-based conclusions about the association between BRCA1 and/or BRCA2 mutation carriership and breast cancer prognosis. We only found sufficient evidence for a 10% worse unadjusted recurrence-free survival for BRCA1 mutation carriers. For all the other outcomes the evidence was judged to be indecisive."
In their concluding remarks, the researchers state, "In contrast to currently held beliefs of some oncologists, current evidence does not support worse breast cancer survival of BRCA1/2 mutation carriers in the adjuvant setting; differences if any are likely to be small. More well-designed studies are awaited."
In order to fully appreciate the implications of these findings one must understand the difference between using breast cancer diagnosis and breast cancer survival as a study end-point. Breast cancer is highly overdiagnosed and overtreated, with recent estimates indicating that about 1.3 million US women were wrongly diagnosed and treated for breast cancer in the past 30 years. And so, previous studies on BRCA1/2 gene variations and the incidence of breast cancer have not taken this massive statistical inflation of non-cancerous "breast cancer diagnoses" into account, further feeding the illusion that having an identified BRCA mutation equates to having a inexorably higher risk of a deadly cancer, when in fact, in cases where BRCA was linked to so-called early stage or 'stage zero' lesions such as Ductal Carcinoma In Situ (DCIS), this condition was recently determined to be intrinsically benign by a NCI-commissioned expert panel and therefore should not be lumped together with other truly deadly forms of breast cancer, as is still common practice today despite the growing body of evidence against it.
The same goes with BRCA-linked ovarian tumors, such as Borderline Ovarian Tumors (BOTs), which are also benign and highly overdiagnosed and overtreated. In fact, a JAMA study found that 5 times more women are diagnosed and treated with ovarian cancer than actually have it -- indicating a massive problem that is not being taken into account by most literature on the role of BRCA mutations in cancer risk because these studies accept diagnosed cancer uncritically as actual cancer which is simply not the case due to the still largely unaccounted for issue of overdiagnosis. Furthermore, prophylactic removal of the ovaries before age 45 (Jolie is 39) has been linked to 67% increased mortality risk, according to a 2006 study published in Lancet Oncology, indicating that organ removal as a generic form of "cancer prevention" may be doing the opposite of 'saving lives' as widely claimed.
And so, what do we take away from this? First, BRCA gene status, based on this recent extensive meta-analysis on the topic, does not necessarily determine your health destiny when it comes to breast (or ovarian) cancer survival. The study found at best, sufficient evidence for a 10% worse unadjusted recurrence-free survival for BRCA1 mutation carriers, but nothing like the oft-quoted 'personalized estimate' of an 87% increase in mortality Jolie received from her doctors and which now many women think is far more common than is the case.
While BRCA gene 'mutations' (technically known a single nucleotide polymorphisms or SNPs, a much less derogatory sounding descriptor) can result in dysfunctional or inactive BRCA protein production, which can prevent our body from healing DNA damage, they also ironically confer certain advantages as far as making the body susceptible to conventional chemotoxic treatments. Also, there is evidence that some of these 'mutations' confer survival advantage, as we addressed in our article, "Did Angelina Jolie Make A Mistake By Acting On The 'Breast Cancer Gene' Theory?":
"BRCA1 variation K1 183R is related inversely to cancer risk, leading the authors of a review on the topic titled, "The case against BRCA1 and 2 testing," to conclude: "It seems that some polymorphisms may actually have a protective effect."
And therefore, what do we really understand about BRCA gene 'mutations' when there are over 500 that have been identified, and whose complexity and role in health and disease are still not yet understood? The truth is that the linear and deterministic gene > trait > disease risk/prognosis way of thinking is archaic, and reflects the type of hubris that should have been sloughed off after the first draft of the human genome project in 2005 found that the 'holy grail' of molecular biology was not to be found in the genome, but in the interstitial space of its interactions with the myriad factors 'beyond the control of the gene,' the realm of epigenetics, which involves everything from the food your mother ate, your in utero exposures, to your breast feeding duration, the toxins and toxicants you were and are exposed to, your way of thinking, attitudes and beliefs and the downstream physiological effects they have, ad infinitum.
Ironically, the notion that genes determine destiny is more than just an idea but a reality for those who believe it and act on the meme, putting ideology into practice in their biology and medical decisions. This is why acknowledging the research that calls into question biological determinism and medical fatalism is so powerful and why we hope our readers continue to explore the primary literature itself as it expands and transforms the often out-dated knowledge base that conventional practice is still under the illusion is reflective of the truth.