Jame Abraham, MD, FACP
EACH YEAR, The ASCO Post asks Jame Abraham, MD, FACP, Director of the Breast Oncology Program at Taussig Cancer Institute and Co-Director of the Cleveland Clinic Comprehensive Breast Cancer Program, to give his picks for the most important research presented at the San Antonio Breast Cancer Symposium. The following are his choices for and comments about studies that may be practice-changing. Dr. Abraham’s comments on these presentations appear in italics.
Role of the PARP Inhibitor Talazoparib
THE PHASE III EMBRACA trial evaluated the investigational poly ADP-ribose polymerase (PARP) inhibitor talazoparib in 431 patients with advanced breast cancer and germline BRCA mutations.1 After a median follow-up of 11.2 months, median progression-free survival was 8.6 months among talazoparib recipients compared with 5.6 months for physician’s choice of therapy (hazard ratio [HR] = 0.54, P < .0001).
Talazoparib demonstrated superior clinical benefit in all key subsets of patients, regardless of receptor subtype, number of prior lines of chemotherapy, BRCA mutation type, and central nervous system metastasis. Improvements in quality of life were also noted, and the drug was well tolerated.
Dr. Abraham: Data from the EMBRACA trial are very promising. A nonchemotherapy agent such as talazoparib may be a better choice than cytotoxic agents in patients with BRCA mutation. In addition to an improvement in progression-free survival, quality of life of these patients was substantially better. Its activity in brain metastases is also impressive.
We see that the concept of PARP inhibition works well in some patients with BRCA mutations. The trick now is to find out who the best responders are (some patients had prolonged responses) and to identify the mechanisms of resistance. If we can do that, this class of drugs may prove to be a real advance in breast cancer.
Sacituzumab Govitecan in Triple-Negative Breast Cancer
IN A PHASE I/II trial, the novel agent sacituzumab govitecan as third-line treatment or beyond led to high response rates in a population of 110 patients with triple-negative breast cancer.2 The drug is an antibody-drug conjugate that consists of SN-38, the active metabolite of irinotecan, linked with a humanized IgG antibody targeted against Trop-2, a cell-surface glycoprotein expressed on more than 90% of triple-negative tumors.
The objective response rate by investigator review was 34%, including three complete responses (31% by blinded independent review, including six complete responses). Of 19 patients who had previously received a checkpoint inhibitor, 9 (47%) responded to sacituzumab govitecan. Nine long-term responders remained free of disease progression for at least 1 year after starting therapy.
Dr. Abraham: This is promising news for patients with triple-negative disease. With this drug, the SN-38 payload is more potent than the parent compound irinotecan, and in vivo studies have shown that the antibody-drug conjugate delivers up to 136 times more SN-38 than irinotecan.
The choice of the camptothecin analog is smart because it has a novel mechanism of action, and it is not cross-resistant with taxanes. Neuropathy is also not a problem with this drug. Because of the need for more effective drugs for advanced triple-negative cancers, sacituzumab govitecan received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for patients with triple-negative disease that has progressed on at least two regimens.
It is possible that the study population was somewhat cherry-picked, since most patients with triple-negative breast cancer don’t make it to the third or fourth round of treatment. Nevertheless, we can hope that future investigations confirm the activity seen in this early study. The phase III ASCENT trial is currently recruiting patients who have received at least two prior regimens, or one or more regimens if they had disease progression within 12 months of completing neoadjuvant or adjuvant therapy. Studies are also evaluating sacituzumab govitecan in combination with other agents.
Dose-Dense Chemotherapy in Early Disease
INCREASING THE DOSE density of chemotherapy lowers the risk of recurrence and breast cancer death by about 15% in women with early breast cancer, according to a large, meticulously conducted meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group.3 The trials included in the meta-analysis achieved dose intensification either by shortening the intervals between chemotherapy cycles or through the sequential administration of anthracycline and taxane chemotherapy. In a pooled analysis of 25 trials involving 34,122 women, a highly significant 15% reduction in recurrence (P = .00001) and a 13% reduction in breast cancer deaths (P = .00001) were found.
Recurrences were noted for 32% of patients receiving standard chemotherapy and 28.4% of those getting dose-dense chemotherapy; mortality rates were 22.2% vs 19.5%, respectively. The dose-dense approaches did not appear to increase toxicity over standard chemotherapy delivery.
Dr. Abraham: Dose-dense chemotherapy is the standard adjuvant chemotherapy for the majority of practices in the United States, but it is not the most commonly used adjuvant regimen outside the U.S. Data from this large meta-analysis suggest that dose-dense chemotherapy should be considered as the most appropriate standard chemotherapy in the adjuvant setting.
Dose-dense chemotherapy not only results in better outcomes, but treatment is given over a shorter time period, which patients like. Some patients do report being more tired with every-2-week cycles, but the length of time they must endure side effects is shorter. Toxicity can be reduced with growth factor support. Everybody wins with this approach.
Adjuvant Trastuzumab in HER2-Low Breast Cancer
NO BENEFIT was found to adjuvant trastuzumab (Herceptin) in patients whose tumors test “low” for HER2 expression—ie, 1+ or 2+ by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) ratio < 2.0.4 Based on earlier studies hinting at a benefit for anti-HER2 therapy in some patients not strictly “HER2-positive,” the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-47 trial was conducted.
The randomized trial in 3,270 patients found absolutely no improvement in invasive disease–free survival, overall survival, or other endpoints when women received 1 year of trastuzumab in addition to standard chemotherapy, vs chemotherapy alone. After a median follow-up of 46.1 months, the 5-year invasive disease–free survival rate was 89.6% for the trastuzumab arm and 89.2% for the control arm (HR = 0.98, P = .90) and overall survival was 94.8% and 96.2%, respectively (HR = 1.33, P = .14).
Dr. Abraham: Based on signals seen in early trials of trastuzumab, for the past decade breast cancer experts have wondered whether women with low levels of HER2 might derive some benefit from the anti-HER2 agent. Most notably, in the landmark NSABP B-31 trial, some patients found to have “HER2-low” tumors by central testing derived a benefit similar to those with tumors confirmed as HER2-positive. The NSABP B-47 trial was designed to evaluate this possibility in a randomized manner.
This was an important question to ask and to answer, and the result was somewhat unexpected. Even patients with IHC 2+ staining enjoyed no more benefit than those with IHC 1+ staining. It’s hard to completely explain these findings, but the bottom line is, based on this very clean, well-conducted study, we should not prescribe trastuzumab to HER2-negative patients. Physicians should simply stick to the guidelines and use trastuzumab only for patients deemed HER2-positive by appropriate testing.
Extended Endocrine Therapy
IN THE AUSTRIAN Breast and Colorectal Cancer Study Group (ABCSG)-16 trial, involving 3,484 postmenopausal patients with hormone receptor–positive early breast cancer, 7 total years of endocrine therapy was deemed the optimal duration of treatment.5 Adding 2 years of aromatase inhibitor therapy after 5 years of adjuvant endocrine therapy with either tamoxifen, an aromatase inhibitor, or the combination of both yielded outcomes that were as good as those with an additional 5 years (ie, 10 total years).
Disease-free survival at 10 years was 71.8% with 2 additional years of therapy vs 70.3% with 5 additional years. No subgroups were identified in which longer treatment was better, including high-risk patients. Overall survival at 10 years was also similar: 85.3% for the 2-year arm and 84.9% for the 5-year arm.
Dr. Abraham: The ABCSG-16 study failed to meet its primary endpoint, but this is actually good news for patients. When we talk to patients about staying on treatment beyond 5 years, perhaps 2 more years will not be so overwhelming. We may be treating too many women for too long, with 10 years of endocrine therapy. It appears we are not depriving patients of benefit if they stop at 7 years.
It is also possible that patients with small tumors, node-negative disease, and/or low-grade cancers may not need extended adjuvant hormonal therapy (beyond 5 years) at all. Ongoing biomarker studies and currently available biomarker tests may help us in identifying the subset of patients who may benefit from extended adjuvant aromatase inhibitor therapy.
Adjuvant Bisphosphonates
THE PHASE III SUCCESS A trial evaluated 5 vs 2 years of adjuvant zoledronic acid treatment in high-risk early breast cancer patients and found no benefit for the longer duration.6 Disease-free survival was the same in each arm—approximately 90% at 40 months, with 129 events in the 5-year arm and 121 events in the 2-year arm (P = .827). Adverse events were more frequent with 5 years of treatment.
Dr. Abraham: Bisphosphonates have been shown to reduce skeletal events in patients with cancer, prevent recurrences to the bone, and improve survival, especially in postmenopausal patients, but the optimal duration of treatment has been unclear. In 2017, ASCO and Cancer Care Ontario recommended zoledronic acid or clodronate (not FDA-approved) every 6 months for 3 to 5 years in postmenopausal patients with breast cancer.
Based on the findings of the SUCCESS A trial, for most women (in the absence of low bone mineral density) 2 years may be sufficient. However, it is also rational to administer the drug longer in women on an aromatase inhibitor (which accelerates bone loss). The SUCCESS A study provides interesting information, but it is not definitive in determining the optimal duration of bisphosphonate therapy for all women.
Pathologic Complete Responses in I-SPY 2
THE ADAPTIVE I-SPY 2 trial demonstrated that the achievement of a pathologic complete response (defined as no residual invasive cancer in the breast or lymph nodes, as determined by the residual cancer burden method 7) is associated with significant improvements in event-free and distant relapse– free survival.8 Of 746 patients, 259 (35%) achieved a pathologic complete response and 487 (65%) did not.
At 3 years, patients achieving a pathologic complete response had a 3-year event-free survival rate of 94%, compared to 76% for patients who did not (HR = 0.20). Distant relapse–free survival rates at 3 years were 95% and 79%, respectively (HR = 0.20). The benefit of pathologic complete response was observed across all breast cancer subtypes. The investigators concluded that pathologic complete response is an appropriate surrogate for clinical outcomes.
Dr. Abraham: The results for patients achieving a pathologic complete response are extraordinarily good. The study clearly validates this outcome after neoadjuvant surgery as a powerful biomarker that can help identify individual patients with an excellent prognosis.
Weight Loss and Breast Cancer Risk
POSTMENOPAUSAL WOMEN who lost weight had a significantly reduced risk for breast cancer in a multivariable analysis from the Women’s Health Initiative observational study.9 Of 61,335 women, 3,061 developed invasive breast cancer over 11 years. Compared to women with stable weight, those who lost at least 5% of their baseline weight were 12% less likely to develop breast cancer. Weight loss of at least 15% was associated with a 37% reduction in risk.
Dr. Abraham: There is an increasing appreciation of the role of obesity in cancer. This study shows that relatively modest weight loss is associated with significant lowering of breast cancer risk. Although we usually see women after they have already been diagnosed, this is information that the general public should be aware of, and oncologists can be informative. We also need to continue to pay more attention to lifestyle intervention in breast cancer survivors. ■
DISCLOSURE: Dr. Abraham reported no conflicts of interest.
REFERENCES
1. Litton JK, Rugo HS, Ettl J, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS6-07. Presented December 8, 2017.
2. Bardia A, Vahdat LT, Diamond J, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 6, 2017.
3. Gray R, Bradley R, Braybrooke J, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 6, 2017.
4. Fehrenbacher L, Cecchini RS, Geyer CE, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 6, 2017.
5. Gnant M, Steger G, Greil R, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 7, 2017.
6. Janni W, Friedl TWP, Fehm T, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS1-06. Presented December 6, 2017.
7. Symmans WF, Peintinger F, Hatzis C, et al: J Clin Oncol 25:4414-4422, 2007.
8. Yee D, DeMichele A, Isaacs C, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS3-08. Presented December 7, 2017.
9. Chlebowski RT, Luo J, Anderson GL, et al: 2017 San Antonio Breast Cancer Symposium. Abstract GS5-07. Presented December 8, 2017.
