August 2013 Ask the Expert: Triple-Negative Breast Cancer Highlights

August 1, 2013

Living Beyond Breast Cancer experts Carey K. Anders, MD, and Hope S. Rugo, MD, answer your questions about triple-negative breast cancerinfo-icon in this companion to our April 2013 webinar and Ask the Expert session.

Question: After the chemo-surgery-radiation treatment for TNBC, what are your thoughts on metformin, diet, exercise, aspirin and anything else to consider with the goal of decreasing risk of recurrence?

Dr. Anders: Following traditional chemotherapyinfo-icon, surgeryinfo-icon, and radiation therapyinfo-icon for TNBC, leading a generally healthy lifestyle is a proactive way to help reduce the risk of recurrenceinfo-icon and to ward off other illnesses.  Studies have shown that regular exercise (approximately 5 times a week) and a healthy diet full of fruits and vegetables (5 servings combined) may reduce breast cancer recurrence. A large retrospective studyinfo-icon of aspirin use also showed that routine use may be linked to lower breast cancer recurrence and, if already on it for cardiovascular health, it is very reasonable to continue.  The data for metformin is somewhat mixed, but some retrospective studies have shown a protective effect of metformin on breast cancer risk.

Question: I was diagnosed with triple-negative breast cancer in 2009 and my doctor told me it has a tendency to recur after treatment. What percentage of TNBCs, would you say, actually recur? My doctor's statement has caused me to live in fear, even though I took chemotherapy at that time and have been clear for 4 years now.

Dr. Anders: Studies have shown that women with TNBC have twice the rate of distant recurrenceinfo-icon as compared with other types of breast cancer.  In contrast to other subtypes of breast cancer, the risk of TNBC recurrenceinfo-icon peaked within 3 years of diagnosisinfo-icon and declined rapidly thereafter. These studies are somewhat limited by their retrospective nature and use of older, possibly outdated, chemotherapyinfo-icon regimens.

Question: Is the percentage of women who get TNBC on the rise? I have heard that only about 12 percent of breast cancer is triple-negative, but I seem to be meeting more and more women with TNBC.

Dr. Anders: In general, TNBC accounts for approximately 15 – 25 percent of all breast cancers and is over-represented among younger women and African-American women. Awareness of TNBC is certainly increasing, but to my knowledge, the incidenceinfo-icon of the disease is not.

Question: Is there any drug on the horizon that shows promise as an adjuvant therapy against the recurrence of triple-negative breast cancer? I would be interested in clinical trials also.

Dr. Anders: At present, the standard of careinfo-icon for TNBC in the adjuvant setting is chemotherapyinfo-icon. Unfortunately, the addition of the anti-VEGF antibody, bevacizumab, to standard adjuvant chemotherapy in the BEATRICE trial did not yield improved outcomes.  Basic scientists and clinicalinfo-icon researchers continue to evaluate other pathways that may be of benefit in this setting.

Question: If TNBC is to recur it is usually in the first 2-3 years and I have heard that at 5 years or beyond there is a better outcome. My question is when do you start to track your anniversary date? The day you were diagnosed, the date after you completed chemotherapy or radiation therapy, or the date you had surgery?

Dr. Anders: In the landmark study that defined the peak of recurrenceinfo-icon at 3 years for TNBC, this was defined as “from date of diagnosisinfo-icon” in the Clinicalinfo-icon Cancer Research article by Rebecca Dent et al. entitled “Triple Negative Breast Cancer: Clinical Features and Patterns of Recurrence.”

Question: How would we know if we have luminal or basal-like triple-negative breast cancer?

Dr. Anders: Presently, there is no clinicalinfo-icon test to differentiate luminal vs. basal-like TNBC. The PAM50® assayinfo-icon, which is a geneinfo-icon-based assay predictive of breast cancer subtype, is being used in the research setting; however, it is not yet clinically available.  One study indicated that close to 40% of cancers that are estrogen receptorinfo-icon/progesterone receptorinfo-icon “low” (as defined as  1 – 10% staining) are actually luminal breast cancers.  Until we have additional tools available in the clinic, the ability to predict luminal vs. basal-like TNBC is restricted to the research setting.

Question: Have you found that Caucasian women are more responsive to chemo than African-American women or that Caucasian women have an increased rate of survival?

Dr. Anders: Studies have not demonstrated TNBC to display differential chemotherapyinfo-icon response by race. In fact, in studies of women with TNBC treated with neoadjuvant chemotherapy, rates of pathologic complete responseinfo-icon by race have been equivalent. 

Question: What percentage of women achieve a complete pathologic response after neoadjuvant therapy for TNBC?

Dr. Anders: While the rates of pathologic complete responseinfo-icon to chemotherapyinfo-icon for TNBC vary by study, rates have consistently been in the 30 – 40% range.  Many studies have illustrated a higher pathologic complete response to chemotherapy for TNBC as compared with other subsets of breast cancer, particularly hormoneinfo-icon-sensitive breast cancers.

Question: Can you talk about next-generation gene sequencing and gene panels and their relevancy to BRCA1 and BRCA2 and breast cancer?

Dr. Rugo: Next-generation sequencing is used to evaluate acquired or somaticinfo-icon geneinfo-icon mutations in cancer cells. BRCA1info-icon and BRCA2info-icon mutations are germline mutations. In other words, they occur in the cells you are born with.  Because next-generation sequencing evaluates changes in cancer-related genes, this testing might pick up an unknown germline BRCA mutationinfo-icon as well, although it this not the standard screeninginfo-icon test for the BRCA inheritedinfo-icon mutations. 

Question: What kind of promise do AE37 trials have?

Dr. Rugo: AE37 is a modified HER2 peptide, or small proteininfo-icon that is linked to an immune stimulant, GM-CSF, to create a vaccine. It has been tested in a clinical trialinfo-icon compared to a different unmodified peptide and to GM-CSF alone in patients with high-risk, early-stage breast cancerinfo-icon that have some expression of HER2. Notably, the cancers can have minimal expression of HER2, but not meet the standard criteria for HER2 positivity.  Preliminary studies with this vaccine are promising, but we need the data from the clinical trial described above in order to really understand the promise of this new vaccine approach. Results should be available in 2014.

Question: Can you please explain the STK11 mutation?

Dr. Rugo: STK11 (also known as LKB1 or liver kinase B) is a geneinfo-icon that makes an enzyme called serine/threonine kinase 11. This enzyme functions to suppress tumorinfo-icon development.  Mutations that cause loss of function in this gene result in the Peutz-Jeghers Syndrome, which is associated with an increased risk of developing a number of different cancers as well as polyps in the bowel. Although breast cancer risk is increased in patients with Peutz-Jeghers, this represents a very, very small fraction of all breast cancers.

Interestingly, recent research has identified a large number of somaticinfo-icon or acquired mutations in the STK11 or LKB1 gene, and these mutations have been found in a number of common cancers including lung, cervical, breast, intestinal, testicular, pancreatic and skin cancers.  This is now of interest as a possible target for treating cancer, or as a markerinfo-icon to predict response to specific targeted therapies. 

Question: Are there studies regarding the likelihood of differences in breast cancer recurrence between people with and without the BRCA gene mutations? There seems to be little info on people with TNBC without BRCA mutations.

Dr. Rugo: It appears that the risk of recurrenceinfo-icon is relatively similar regardless of whether you are born with a mutationinfo-icon in a BRCA geneinfo-icon.  The risk of developing a new breast cancer is higher in women with BRCA mutations, but this does not affect the risk of having an already-diagnosed cancer return in other parts of the body. Recent data suggest that cancers with BRCA mutations may be more sensitive to specific types of chemotherapyinfo-icon or novel agents that cause damage to tumorinfo-icon cellinfo-icon DNA or prevent repair from chemotherapy-induced damage, but this is still being confirmed in ongoing research. 

Question: Dr. Sledge mentioned that it is beneficial to lower total dietary fat. Does this include all types of fat? Monounsaturated fat? Polyunsaturated fat? Saturated fat? I tend to include olive oil in my diet... should I exclude all fat?

Dr. Rugo: One randomized study that evaluated the effect of diet change on outcomeinfo-icon after breast cancer suggested that lower intake of fat could be associated with less recurrenceinfo-icon.  However, women who adhered to a lower intake of dietary fats also lost weight, which might also have a positive effect on recurrence risk.  Another large study that evaluated a diet high in fruits and vegetables compared with standard dietary information found no difference in risk of recurrence.  A diet with a lower intake of saturated fats has many health benefits, so is recommended regardless of whether a person has been diagnosed with breast cancer.  Olive oil is a healthy form of fat that does not appear to be harmful in the amount usually ingested in the diet.

Question: How does it affect your prognosis if you have TNBC but tested negative for the BRCA mutation?

Dr. Rugo: The prognosisinfo-icon of TNBC is related to the extent of cancer at diagnosisinfo-icon, and the biology of that cancer, which determines its responsiveness to chemotherapyinfo-icon. The BRCA mutationinfo-icon may make these cancers more sensitive to chemotherapy agents that damage tumorinfo-icon DNA, but it appears that a number of TNBCs without BRCA mutations are also sensitive to these chemotherapy agents.  Researchers are working on a test to try to figure out which TNBCs are more sensitive to specific types of chemotherapy.  At the present time, prognosis appears to be similar regardless of whether the TNBC is associated with an inheritedinfo-icon mutation in a BRCA geneinfo-icon or not. 

Question: If BRCA1 is linked to TBNC, what about BRCA2 & TNBC? Different follow-up? What is the best source of information?

Dr. Rugo: Most but not all BRCA1info-icon-associated cancers are triple-negative, but a proportion are estrogen receptor-positiveinfo-icon.  The same is true in reverse for BRCA2info-icon mutations: most cancers are estrogen receptor-positive, but some are triple-negative. Treatment and follow-up should be based on the biology of the diagnosed cancer, not only the BRCA mutationinfo-iconPreventioninfo-icon or prophylaxisinfo-icon is based on the risks associated with the inheritedinfo-icon BRCA mutation.

The best sources of information are the NCIinfo-icon website, the American Cancer Center, LBBC, and others.

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