Cancer and Your Genes

Brewing Turf War Between Breast Surgeons and Plastic Surgeons Over Breast Reconstruction

The Wall Street Journal Health Blog has an interesting story on a brewing turf war between breast surgeons and plastic surgeons over breast reconstruction procedures.

Some women with breast cancer - including some with BRCA1 or BRCA2 mutations undergoing bilateral mastectomy - decide to have breast reconstruction performed.  This procedure has generally been performed by a plastic surgeon in a separate procedure from the mastectomy itself.  Now, as noted by the WSJ, a growing number of breast surgeons (without plastics training) are learning the breast reconstruction procedures and beginning to offer it at the same time as the mastectomy itself. 

Undoubtedly, this will lead to some turf wars.  If you are shopping around for a breast reconstruction surgeon, the most important question to ask is how many breast reconstruction procedures have they done...

Where You Get Your Mammogram Matters!

A research group led by Dr. Stephen Taplin of the National Cancer Institute has published a paper in the June 18th issue of the Journal of the National Cancer Institute that assesses whether certain factors differing between mammography facilities are associated with better interpretive accuracy on screening mammograms.

The bottom line is that there are several things that were signficant.  Sensitivity, the ability to detect breast cancers, was quite high and varied little.  However, specificity and positive predictive value varied significantly between sites.  Thus, it seems that the degree to which sites may be "overcalling" their reads (presumably to avoid missing something) varies. 

The following mammography facility traits were associated with better interpretive accuracy for screening mammography:

• Performing only screening mammography at the facility (as opposed to screening plus diagnostic mammography)
• Having a breast imaging specialist interpreting the mammograms
• Not performing double reading of mammograms (more false positives when read by more than one radiologist)
• Conducted audit reviews 2 or more times per year (where individual radiologist-level performance data is shared with the radiologist)

The authors note that it was surprising that double reading did not improve overall test accuracy and that this contrasts with the results of randomized clinical trials.  It may be that double reading methods differ or have been implemented differently in typical clinical practice environments outside of clinical trials.  This deserves a closer look in the future.  Given the relatively weak effect of this predictor of performance, the authors suggested that it should not be utilized to differentiate amongst facility performance until further detailed research is done to sort out the controversy.

It is important to keep in mind that the above factors affected specificity and positive-predictive value primarily.  The authors point out that whether sensitivity or specificity is most important in picking a mammogram facility is dependent on a value judgment.  That is, some women may be most concerned about sensitivity at all costs (i.e., a higher false positive rate leading to a biopsy does not matter).  Other women may wish to consider factors like those noted above that affect specificity and positive predictive value (i.e., they would like to avoid unnecessary biopsies while keeping sensitivity high). 

The results of this retrospective study should be confirmed elsewhere before they are utilized for decision-making.  Nevertheless, you may want to have a dialogue with your physician about mammography facility choice.

Mechanism of Cisplatin-Resistance in BRCA2-Related Ovarian Cancers

Our increasing molecular knowledge of the pathways involved in cancer development continues to suggest potential avenues for molecularly-targeted cancer therapies.  However, aside from a few examples (Gleevec, Herceptin, and others), molecularly-targeted therapy is still not a reality for most cancer types.

Individuals born with mutations in the BRCA2 gene have a substantially elevated lifetime risk for breast cancer, ovarian cancer, and several other cancers.  Recent work has shown that loss of BRCA2 function results in defects in a DNA repair process called "homologous recombination."  Evidence has emerged that PARP-inhibitor drugs, which are currently under development as possible treatments for BRCA2-associated cancers, are potent killers in vitro of cells lacking BRCA2.  In fact, the loss of homologous recombination capacity in BRCA2 mutant cells is thought to be an achilles heel that may be exploited both by PARP-inhibitors and also by platinum compounds such as cisplatin (BRCA2-mutated ovarian cancers seem to be particularly sensitive to cisplatin). 

However, individuals treated with another molecularly-targeted therapy, Gleevec, for chronic myelogenous leukemia have developed resistance to the drug in some cases.  Indeed, individuals with BRCA2-related ovarian cancers ultimately develop cisplatin resistance. 

Two papers published online today in the journal Nature (abstracts available here and here) show us why this is the case at least in a subset of cases in individuals with BRCA2 mutations.  Basically, various revertent mutations can occur under selection of cisplatin or PARP-inhibitors that result in expression of a functional BRCA2 protein again that improves the cellular capacity to promote homologous recombination, thus eliminating the achilles heel.  Thus, BRCA2 loss is involved in the establishment of the cancer, but is not necessary for its maintenance (especially under the selective pressure of treatment with Cisplatin).

This has a number of implications:

• Genotyping of tumors in individuals with BRCA2 mutations may help to predict whether PARP-inhibitors or platinum-containing compounds are likely to be effective in their treatment
• BRCA2-associated tumors that have acquired PARP/cisplatin-resistance may be treatable with a combination of cisplatin or a PARP-inhibitor plus a secondary drug disrupting homologous recombination
• Although PARP-inhibitors have not yet reached the clinic, we now know of one potential challenge in their potential use
• As some sporadic ovarian cancers seem to have lost BRCA2 function, these findings may be relevant to understanding treatment resistance even in some ovarian cancers that apparently are not hereditary