This year at the San Antonio Breast Cancer Symposium (SABCS) there were two aspects of breast cancer that were clearly emphasized: use of ovarian suppression in premenopausal women with breast cancer and advances in genetic testing for hereditary cancer predisposition.
Results of the SOFT trial (further detailed by Dr. Wade Smith in this post), show a clear benefit to the addition of ovarian suppression in women under the age of 35. This benefit resembles that seen with the addition of Herceptin for HER2+ cancer, and now calls for a change in practice management.
The second “call for action” released at the SABCS in a variety of forms, from lectures, discussion panels, vendors, and posters, was the rise of expanded panels of genetic testing and the implications for patients and clinicians.
Photo courtesy of the Lasker Foundation.
Most notably, Dr. Mary Claire King, award recipient of the 2014 Lasker-Koshland Award for Special Achievement in Medical Science for the discovery of the BRCA1 gene locus that leads to hereditary breast cancer, delivered a landmark speech. Dr. King called for routine genetic testing for all women age 30 and above, regardless of family history.
While this concept will not change practice overnight (nor will this kind of “blanket” testing immediately be covered by insurance companies in the United States), it has clearly stirred all of us to think about cancer genetics and risk assessment at a higher level.
In this post, we will review several key updates presented at 2014 SABCS.
- Breast cancer prevention: results of the IBIS II trial, results of the WINS trial, and a review of the studies evaluating risk factors for second breast cancers.
- Breast cancer screening: lessons learned from the Connecticut Experiment, which added screening ultrasound to all women with dense breasts.
- Genetic Testing—risks and benefits of panel testing, background to Dr. King’s call for action, and BRCA-treatment related trials.
Breast Cancer Prevention
Anastrozole: A potential option for breast cancer prevention
Women with high risk for developing breast cancer based on family history and/or personal history of a high-risk lesion, such as atypical ductal hyperplasia, can reduce their risk of breast cancer using anti-hormone blockade with Tamoxifen.
The International Breast Cancer Intervention Study-II (IBIS-II) followed close to 4,000 high-risk women who were randomized to anastrozole, an aromatase inhibitor (AI), versus a placebo for a median of five years. Women given the AI experienced a 53 percent reduction in breast cancer compared to the control group. Results indicated that women taking anastrozole may also experience fewer side effects than with other preventive drugs.
Obesity & Breast Cancer Risk
It is well established that women who are obese with a history of breast cancer have a higher risk of breast cancer recurrence and death than their non-obese counterparts. The Women’s Intervention Nutrition Study (WINS) was a randomized clinical trial evaluating the benefit of strict dietary intervention with a reduced fat intake compared to baseline nutrition counseling.
Women in the intervention group were guided to achieve a dietary fat intake of 15% of total calories, whereas baseline intake was close to 30% for all participants.
Women in the intervention group were able to significantly reduce their dietary fat intake, sustain an average weight loss of 5.5 pounds and achieve a 24 percent reduction in relapse-free survival at the end of 5 years. After nearly 20 years of follow-up now, women in the intervention group had fewer deaths compared to the control group (13.6 percent versus 17 percent).
However, this did not achieve statistical significance. Interestingly, women who received the greatest benefit in the intervention group had ER-negative breast cancer, indicating that obesity is not a risk factor just for hormone-sensitive cancers.
Risk for Breast Cancer Recurrence
In an excellent review of dozens of studies on breast cancer recurrence and risk factors, Dr. Christopher Li presented data on a number of factors related to either an increase or decrease of developing a second breast cancer.
Factors that increase the relative risk of a second breast cancer include having an elevated Body Mass Index (BMI), smoking, drinking more than one drink per day and having diabetes. Factors that decrease the risk of a second cancer include use of bisphosphonate therapy (most frequently in the setting of osteoporosis) and the use of tamoxifen (See Table I for relative risks).
Again, at this conference, there were a number of posters showing the potential benefit of the drug metformin, used commonly in patients with diabetes, in the outcomes of patients with breast cancer regardless of whether or not they have overt diabetes.
This underscores the importance of preventing an underlying state of inflammation that occurs with both obesity and diabetes in the prevention of future breast cancers. Much more of this concept will continue to be seen in future conferences.
Table I. Factors Related to Risk of Second Breast Cancer:
(*Relative risk of 1.0 means no influence, greater than 1 indicates an increased risk while less than 1 indicates a decrease in risk. All risks reported are statistically significant in one or more studies.)
Breast Cancer Screening
The Connecticut Experiment
Breast density has been an important focus for researchers and clinicians alike for a number of decades. Women with dense breasts have a four-fold increased risk of developing breast cancer and are more likely to have a breast cancer that cannot be detected easily with mammography alone.
In 2009, Connecticut was the first state to pass a law mandating all women be informed if they have dense breasts based on their mammogram. Unlike the California breast density notification law that went into effect several years later, the Connecticut law mandated that insurance companies cover supplemental screening with either ultrasound or MRI.
Dr. Jean Weigert, presented four years’ worth of data from the “Connecticut Experiment,” which reviewed the screening results from 5 practice sites in Connecticut. All women undergoing screening mammography who had breasts with 50% or greater density on mammography were allowed to have screening breast ultrasound delivered by hand-held ultrasound.
In each year, there was an increase in cancer detection rate of 3.2 per 1000 with the addition of supplemental screening ultrasound. The additional cancers detected were all early stage, with the majority being Stage I, low-grade, and hormone receptor positive. This is similar to the results of the ACRIN 6666 trial. There was a higher positive predictive value (PPV), or percentage of biopsies yielding cancer, by year four at 18%.
This indicates there was a learning curve for radiologists. However, this “improvement” in PPV was accounted for by an increase in the number of women in year four being asked to return in 6 months for short-term follow-up imaging. Interestingly, while screening ultrasound was covered by insurance companies, only 30% of women who qualified for this screening modality actually presented for testing.
Trade-offs to supplemental screening?
The main issue with these results are determining whether or not the benefit of identifying 3 to 4 more breast cancers per 1000 women screened is worth the anxiety of many more negative (benign) biopsies and an increase in cost to both patients and payors alike.
An even more provocative question is whether tomosynthesis, or 3D mammography, is “better” than screening ultrasound as this modality lowers recall rate and has a much higher PPV.
For now, we encourage all women with extremely dense breasts, a category of density that even tomosynthesis cannot sufficiently help us with, to consider supplemental screening breast ultrasound or MRI if indicated. We are also very fortunate to already have tomosynthesis at three of our centers, an imaging modality the rest of the country is slowly, but uniformly, adopting.
Genetic Testing and PARP Inhibitors
There has been a revolution of change over the past two years in genetic testing for hereditary cancers. Three main advances have allowed for this revolution:
- The understanding of germ-line (inherited) genetic mutation events in their relationship to cancer progression has increased our ability to identify more genes that can be implicated in familial cancers.
- Next generation sequencing has made it technically feasible to rapidly sequence numerous genes at once from a single blood sample.
- The Supreme Court overturn of a patent on BRCA1/2 gene testing has enabled numerous companies to drive the market price of genetic testing down and make it more available to people at risk.
What we are now seeing is more testing of more women for more genes. This is “panel testing” or looking at an array genes that may be implicated in certain familial cancer syndromes (i.e., breast cancer, ovarian cancer, colon cancer, etc.), rather than limited testing of only one or two genes at a time. This will enable us to identify more people at risk and will help us better understand some of the patterns of cancer seen in families.
The flip-side of panel testing is that we are entering an area of more uncertainty with limited data on the degree of cancer risk associated with some gene mutations, lack of guidelines for risk management with some mutations, and an increase in variants of uncertain significance—gene sequence variability that is not yet classified. Appropriate pre-test and post-test counseling is necessary to ensure this level of uncertainty is relayed to patients.
This year at SABCS, “panel-testing” was a buzzword and many posters, talks, and vendors brought this to the forefront. At the same time, Dr. Mary Claire King spoke of the importance of BRCA 1/2 genetic testing for all women age 30 and over, stating that by identifying a BRCA mutation before a cancer diagnosis occurs can save lives through preventive surgery.
She explained we need to figure out how to drive the cost of testing down even further, and make this part of routine surveillance since the consequences are so great.
Lastly, the importance of knowing about BRCA mutation status was revealed in two aspects of treatment, as well. The results of the TNT trial, which evaluated the sensitivity of platinum-based chemotherapy in triple-negative breast cancers, revealed that BRCA-mutation carriers with triple-negative breast cancer are more sensitive to this drug than non-carriers.
In addition, PARP inhibitors, such as Olaparib and Veliparib, which are showing good response in patients with BRCA-mutations and metastatic breast cancers, are now being phased into neoadjuvant trial settings to evaluate their ability to provide a pathologic complete response.
San Antonio Breast Cancer Symposium 2014
I am excited to have been part of this insightful learning experience. Ongoing breast cancer research and new discoveries are of utmost interest to myself and the rest of the Breastlink physicians. The 2014 San Antonio Breast Cancer Symposium revealed fascinating information and I am hopeful about the potential for new ways of preventing and treating breast cancer.