SABCS Highlights Include Findings in Triple-Negative Disease, Protective Effects of Exercise, and the Adherence-Copay Link


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Kimberly I Blackwell, MD/©ASCO/Todd Buchanan

Dawn L Hershman, MD, MS

Thomas B. Julian, MD

The San Antonio Breast Cancer Symposium brings together specialists from all over the world who focus on management of breast cancer. We have covered many of the important presentations in the pages of The ASCO Post and in our online Evening News. Below are summaries of additional noteworthy meeting highlights. We hope you will find them of interest.

Actionable Genetic Mutations in Triple-Negative Breast Cancer

Mutational analysis of tissue samples of triple-negative breast cancer identified several actionable mutations by genetic sequencing.1 The study included samples from primary tumors and metastatic sites in patients with metastatic triple-negative breast cancer enrolled in a phase II study of carboplatin and paclitaxel as first-line therapy.

The investigators obtained 102 unique samples for genomic sequencing; 29 were triplets of germline/primary tumor/metastatic site, and 6 were doublets of normal and primary DNA. Thirty-one metastatic biopsies were obtained from the liver or nonbreast chest wall metastatic disease.

The majority (91.4%) of somatic mutations were found in both the primary tumor and the recurrent/metastatic samples. Serial biopsies from the same patient revealed mutational changes that occurred only in metastasis in 8.6% of tumors.

Specific gene mutations correlated with clinical outcome and suggest therapeutic targets. For example, four genes were associated with poor response to therapy and unfavorable progression-free survival—WNK1, TP53, JAK1, DCHS2—whereas two genes were associated with more favorable progression-free survival—ATXN7 and MST1. Four of these genes were related to microtubule metabolism and will be studied further.

Genes that correlated with favorable prognosis or longer disease-free interval included HGF, PLXNA3, CSDE1, and ZNF710. Four genes were associated with overall survival: three with unfavorable survival (TP53, ITSN2, and ADH8A1) and one with improved overall survival (SPHKAP). TP53 was the only mutation that conferred both a worse progression-free and overall survival.

Potential actionable mutations and treatments (in parentheses) currently being studied in breast cancer include the following: TP53 (vaccine, gene therapy, WEE-1 inhibitors, Kevetrin); PARP (PARP inhibitors); ESR (alternative endocrine therapy); JAK1 (JAK1 inhibitors); and mTOR (mTOR inhibitors).

“Further chromosomal rearrangement/loss, mutation activation status, and transcriptional analysis for this tissue set is underway,” said lead author Kimberly L. Blackwell, MD, Professor of Medicine and Assistant Professor in Radiation Oncology at Duke University School of Medicine, Durham, North Carolina. This list is by no means exhaustive, she noted. Other genes with potentially actionable mutations are under study by several groups of investigators.

Protective Effect of Exercise in African American Women

Regular vigorous exercise protects against subtypes of aggressive breast cancer, according to a 20-year observational study of more than 44,700 African American women aged 30 years or more called the Black Women’s Health Study.2 Brisk exercise for an average of 3 or more hours a week was associated with a 47% reduced risk of developing estrogen receptor–negative breast cancer compared with exercise for an average of 1 hour per week.

“These findings are encouraging. Knowing that exercise may protect against these cancers that disproportionately strike African American women is of great public health importance,” said lead author Lucile Adams-Campbell, PhD, Associate Director of Minority Health and Health Disparities Research at Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC.

Estrogen receptor–negative subtypes include HER2-positive and triple-negative breast cancer, both of which are more frequent and have higher death rates in African American women compared with Caucasian women. Estrogen receptor–negative tumors are typically more difficult to treat than estrogen receptor–positive ones.

Any level of exercise did not appear to impact the development of estrogen receptor–positive tumors in this study. The authors said that the study was not designed to demonstrate an effect on less aggressive tumors.

The authors hope that this study will encourage black women to exercise. “Along with other well known benefits, we now show that exercise can possibly stave off development of potentially lethal breast cancer in African American women,” Dr. Adams-Campbell stated.

Generic Aromatase Inhibitors

A large study was conducted to determine the impact of the change from brand name to generic aromatase inhibitors on adherence and discontinuation among breast cancer patients prescribed hormonal therapy.3 Results showed that out-of-pocket costs had an independent and linear association with adherence and discontinuation. Generic aromatase inhibitors were also independently associated with both improved adherence and lower rates of discontinuation.

“These findings suggest that breast cancer survival may be improved by increasing access to medications,” said lead author Dawn L. Hershman, MD, MS, Associate Professor of Medicine at Columbia University Medical Center in New York. “Patients, providers, and advocates should be aware of the Cancer Treatment Fairness Act to prohibit higher copayments regardless of benefit category,” she told listeners.

The study was based on the Optum database (25 million members of United Health Care), Medicare (6 million members), and Medicaid (2 million members) and included women with early-stage breast cancer diagnosed between 2001 and 2011 who were older than age 50 and who filled two or more prescriptions for hormonal therapy (tamoxifen, or brand name or generic aromatase inhibitors).

Among 13,522 patients, 7,500 did not switch hormonal therapy during the study period while 5,990 switched therapy at some time (72% switched from brand name aromatase inhibitors to generic aromatase inhibitors). Among nonswitchers, 89% had commercial insurance and 84% had no deductible.

A multivariate analysis showed that generic aromatase inhibitors had significantly lower rates of discontinuation vs brand name aromatase inhibitors (P = .001). No difference was observed for discontinuations between tamoxifen and brand name aromatase inhibitors.

 A linear relationship was found between copayment amount and discontinuation, with copayments of $20 or more significantly associated with discontinuation (P < .001). In addition, annual income was associated with adherence, with those at the highest income level (> $100,000 per year) significantly more adherent than those with annual incomes < $40,000 (P = .003).

Occult Metastases Not Clinically Important in Node-Negative Breast Cancer

The 10-year follow-up of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 study, which examined outcomes for 5,611 clinically node-negative breast cancer patients randomly assigned to sentinel node dissection or sentinel node dissection plus axillary dissection, was reported in San Antonio by Thomas B. Julian, MD, Senior Surgical Director of NSABP Medical Affairs and Professor of Surgery at Temple University, Allegheny General Hospital, Pittsburgh.4 Occult metastases were found by immunohistochemistry (IHC) in 616 patients (16.4% of the axillary dissection group and 15.3% of the sentinel node–only dissection group). The majority of these metastases (11%) were isolated tumor cells.

At 10 years, there continued to be no significant difference between sentinel node dissection and sentinel node plus axillary dissection in terms of overall survival, disease-free survival, distant disease–free survival, or regional control for patients with histologically node-negative disease by strict hematoxylin-and-eosin (H&E) analysis, he reported. Overall survival was approximately 90% per arm, and disease-free survival was about 77%.

In an analysis of overall survival according to the presence or absence of occult metastases, the difference between the arms—which was statistically significant at 8-year follow-up—was no longer statistically significant. Overall survival rates were 89% for patients without occult metastases and 85.9% for those with occult metastases, a 3.1% difference (hazard ratio [HR] = 1.26, P = .06).

However, the study identified a significant difference in disease-free survival between the groups, with a 4.7% absolute lower 10-year rate for those with occult metastases (HR = 1.25, P = .01).  The difference in local-regional recurrence-free interval was not significant, with a 1.4% absolute lower 10-year rate for those with metastases (HR = 1.32, P = .17). 

“The impact of occult metastatic nodal disease in this very large cohort of 5,611 patients is clinically nonsignificant,” according to Dr. Julian. “Overall survival, disease-free survival, and local-regional recurrence is not affected by the 15.3% positive occult metastases in the sentinel node resection–only group. Axillary node dissection for occult metastases is of no benefit.”

5-FU Not Beneficial as Adjuvant Therapy

The randomized phase III GIM-2 trial found no benefit for adding fluorouracil (5-FU) to standard chemotherapy for early node-positive breast cancer.5 The key finding, according to Francesco Cognetti, MD, a medical oncologist at the Regina Elena National Cancer Institute in Rome, is that “5-FU should be deleted” from anthracycline-taxane combinations in the adjuvant treatment of node-positive disease. It has not been clear whether adding 5-FU to an adjuvant regimen would be of value, and these results put the issue to rest.

GIM-2 evaluated 2,091 patients treated with epirubicin and cyclophosphamide, with or without 5-FU, followed by paclitaxel given either every 2 or 3 weeks. After a median follow-up of 7 years, a multivariate analysis showed that the dose-dense arms improved both disease-free and overall survival, but adding 5-FU had no effect on clinical outcomes, regardless of the dosing schedule.

The 5-year relapse-free survival rate was 81% in the dose-dense arms and 76% for the standard arms (HR = .78, P < .001). The overall survival rate at 5 years was 94% and 89%, respectively (HR = .69, P = .0001). The accelerated dosing improved disease-free survival regardless of clinical and pathologic characteristics, Dr. Cognetti reported, making it “the optimal option” for early-stage, node-positive disease. ■

Disclosure: Drs. Blackwell, Adams-Campbell, Hershman, and Julian reported no potential conflicts of interest.

References

1. Blackwell KL, Hamilton EP, Marcom PK, et al: Exome sequencing reveals clinically actionable mutations in gthe pathogenesis and metastasis of triple negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S4-03. Presented December 12, 2013.

2. Adams-Campbell L, Palmer JR, Bethea T, et al: Vigorous exercise across the lifespan and reduced risk of estrogen receptor negative breast cancer in African American women. 2013 San Antonio Breast Cancer Symposium. Abstract PD2-7. Presented December 11, 2013.

3. Hershman D, Tsui J, Meyer JW, et al: The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early stage breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 12, 2013.

4. Julian TB, Anderson SJ, Weaver, et al: 10-yr follow-up results of occult detected sentinel node disease: NSABP B-32. 2013 San Antonio Breast Cancer Symposium. Abstract S2-05. Presented December 11, 2013.

5. Cognetti F, Bruzzi P, De Placido S, et al: Epirubicin and cyclophosphamide followed by paclitaxel versus fluorouracil, epirubicin and cyclophosphamide followed by T, all given every 3 weeks or 2 weeks, in node-positive early breast cancer patients. Final results of the Gruppo Italiano Mammella (GIM)-2 randomized phase III study. 2013 San Antonio Breast Cancer Symposium. Abstract S5-06. Presented December 13, 2013.



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