Breast cancer after prophylactic mastectomy?

“You have breast cancer” are the last words any woman wants to hear. But women facing hereditary breast and ovarian cancer risk who opt for prophylactic mastectomies hope never to hear these words. Avoiding breast cancer is why these women take dramatic action to reduce risk. So when a new study comes out that may indicate that residual breast cancer risk is higher than previously thought, alarm bells start sounding in the high-risk community. The journal Clinical Genetics did publish such a study recently. This study, entitled Breast cancer after bilateral risk-reducing mastectomy is based on research out of Denmark involving 307 BRCA-positive women, 96 of whom chose to have prophylactic bilateral mastectomies to reduce their risk.

On one level, the study’s finding are concerning. Three of the 96 women developed breast cancer 2 years, 5 years, and 7 years after prophylactic mastectomy respectively. All of these women were BRCA1 positive and all of the cancers were triple negative. These numbers led the researchers to alarming conclusion that the breast cancer risk after preventive mastectomy for BRCA-positive women is roughly 10 percent, almost the same level of risk as the average risk women.

It is easy to panic when confronted with this conclusion but a closer look at the study, its assumptions, and other studies of breast cancer risk after prophylactic mastectomy are necessary to gain some perspective on the issue. It is dangerous to focus exclusively on any one study, especially when it has a relatively small sample size.

We are in early days for the results of studies that estimate the residual breast cancer risk of BRCA-positive women after prophylactic mastectomies with only a handful of studies having been published thus far. The largest study to date involving 2482 BRCA-positive women analyzed the effect of both prophylactic mastectomy and prophylactic bilateral salpino oophorectomy on future cancer risk.  This study, entitled Association of Risk-Reducing Surgery in BRCA1 and BRCA2 Mutation Carriers With Cancer Risk and Mortality, was published in the Journal of the American Medical association September 1, 2010 and we blogged about it in our post Beyond the headlines: Prophylactic surgery reduces cancer risk and saves lives. Interestingly, in this study 247 women chose to have prophylactic mastectomies and none of them developed breast cancer, which resulted in the conclusion that prophylactic mastectomies are highly effective at reducing breast cancer risk in BRCA1 and BRCA2-positive women. BUT the study made no attempt to statistically quantify the remaining breast cancer risk because such a calculation was not possible given no breast cancer events in the preventive mastectomy group.

A 2004 U.S. study had results more similar to the Danish study. It involved 483 BRCA-positive women 105 of whom chose prophylactic mastectomies. Two women in this study developed breast cancer after preventive mastectomies, one was diagnosed with breast cancer in her lymph nodes less than 2 years after her preventive mastectomies and the other was diagnosed with breast cancer 9 years later in what was described as "significant residual right breast tissue" that had been left after the prophylactic mastectomies.

Statistical analysis of risk reduction in these studies is complex business involving a discipline called biostatistics.  In calculating the final residual risk number the statistical analysis involves a number of assumptions and complex calculations involving the raw data. Changes in any of the assumptions will change the end result and may account for why the Danish study resulted in a seemingly large residual risk analysis.  We leave the statistical analysis to the mathematicians but raise this as one thing to consider when confronted with a study conclusion that seems alarming.

Unfortunately, more years of follow-up and more published studies are needed before the experts will have a good handle on the amount of breast cancer risk that remains after preventive mastectomies.

What lessons can be learned from the research so far?

While the conclusion from this new Danish study should probably be taken with a grain of salt, it nonetheless raises issues that women should discuss with their doctors and one thing is clear: prophylactic mastectomy does not totally eliminate breast cancer risk.

Another thing that comes through from the studies to date is the suggestion that the residual risk is directly affected by the amount of breast tissue left by the breast surgeon performing the surgery. In the 2004 U.S. study, both of the post-mastectomy breast cancers occurred after subcutaneous mastectomies, which generally leave behind a greater amount of breast tissue than does a simple mastectomy. In the Danish study all three of the women who developed cancer had simple mastectomies but the study authors nonetheless placed most of the blame on breast tissue that should have been removed. One of the three breast cancers occurred two years after the mastectomies and was already metastatic with a small tumor in the residual breast tissue that the breast surgeon had not removed in the axilla (under the arm). The study authors speculated that because of the presentation it was likely that the cancer either had been present at the time of the prophylactic mastectomies but was not found by the pathologist or that it subsequently developed in the breast tissue under the arm that had not been removed. The study authors concluded that “inadequate surgery” was the probable cause of the other two post-mastectomy cancers.

On the other hand, the 2010 JAMA study authors noted that their “observation of no prospectively identified breast cancer cases may be due to biases in prior retrospective studies or to improved surgical techniques.” Further studies will hopefully determine whether surgical technique and/or skill of the breast surgeon play a role in residual risk. The studies to date suggest that maximum risk reduction likely comes from high-risk women being treated by highly-skilled specialists who remove the maximum amount of breast tissue. If this proves to be true, women considering prophylactic mastectomies may need to choose their breast surgeon even more carefully than they choose their reconstructive surgeon.



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