Correlative science studies, evaluation of residual cancer burden, and long-term outcomes may help define the role of estrogen deprivation in the treatment of HER2-positive early breast cancer.— Mothaffar F. Rimawi, MD
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The addition of estrogen deprivation to neoadjuvant chemotherapy and HER2 blockade did not enhance the achievement of pathologic complete responses in women with early-stage breast cancer, according to the results of the NRG Oncology/NSABP B-52 trial reported at the 2016 San Antonio Breast Cancer Symposium by Mothaffar F. Rimawi, MD, of Baylor College of Medicine, Houston.1
NRG Oncology incorporates the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG).
“Preclinical evidence shows that tumors that are estrogen receptor–positive and HER2-positive are less likely than estrogen receptor–negative/HER2-positive tumors to respond to dual anti-HER2 therapy,” Dr. Rimawi revealed. “We think the estrogen receptor may act as a pathway of resistance to anti-HER2 treatment. From older trials, there were concerns about the potential antagonism of chemotherapy and tamoxifen, but data combining newer agents have not been available.”
The hypothesis of the NRG Oncology/NSABP B-52 trial was that concurrent inhibition of the estrogen receptor and HER2, plus chemotherapy, would not be antagonistic and would overcome resistance to treatment. As a result, it should improve pathologic complete responses in patients with estrogen receptor–positive/HER2-positive breast cancer, Dr. Rimawi explained.
Large Prospective Study
The B-52 trial enrolled the largest prospective cohort of patients to be treated with docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta; TCHP). The study included 315 patients with HER2-positive, hormone–receptor positive invasive breast cancer. This was a high-risk population, with almost half the patients younger than age 50, one-fourth of patients having clinical T3 or T4 disease, and more than half of patients having positive lymph nodes.
Patients were randomized to receive neoadjuvant treatment with TCHP or TCHP plus estrogen-deprivation therapy. This was an aromatase inhibitor for postmenopausal women and an aromatase inhibitor plus ovarian suppression for premenopausal women. Dr. Rimawi emphasized that these patients would all receive endocrine therapy at some point (here, in the neoadjuvant setting or as adjuvant therapy). “We are just moving up the time line,” he said.
Patients received six cycles of treatment and then underwent surgery. The primary endpoint was achievement of pathologic complete response in the breast and lymph nodes. The investigators expected the pathologic complete response rate in the control arm (no estrogen deprivation) to be 45%, based on the TRYPHAENA trial.2 Other regimens involving anthracyclines have produced numerically lower rates, he noted.
No Improvement With Estrogen Deprivation
The pathologic complete response rate in the overall population was 41% with TCHP and 46% with TCHP plus estrogen deprivation (P = .39). “This numerical increase was not statistically significant,” Dr. Rimawi reported.
By menopausal status, pathologic complete responses were achieved by 44% with TCHP and 46% with TCHP plus estrogen deprivation in the premenopausal group (P = .80) and by 38% and 45%, respectively, in the postmenopausal group (P = .33). Similar trends were shown for pathologic complete responses in the breast and nodes as well as the breast alone.
“Overall, the rate of toxicity was quite high—over 60% grade 3/4—but there were no differences between the arms,” he reported. This included considerable gastrointestinal toxicity (diarrhea, nausea, vomiting, and dehydration), anemia, and hypokalemia. Febrile neutropenia occurred in about 6% of the control arm and 8% of the estrogen-deprivation arm.
Further Research Needed
“The addition of estrogen deprivation to neoadjuvant chemotherapy was not, however, antagonistic, and it did not increase toxicity,” Dr. Rimawi commented. Although the aim was to improve upon the response rates achieved with TCHP alone, the study at least showed no compromise with the addition of endocrine therapy. “To a certain extent, at least the numeric increase probably allays concerns over antagonism,” he admitted.
“Most important, given the toxicity of standard chemotherapy observed on this trial,” Dr. Rimawi added, “the findings from NSABP B-52 argue for a tailored de-escalation approach, where toxic treatments are omitted or replaced with less toxic ones without compromising outcomes.”
In tumors with multiple targets, the question will be whether chemotherapy can be less extensive or even eliminated for some subsets. Long-term follow-up would be needed to confirm that such a de-escalated approach does not compromise outcomes, he said.
“Correlative science studies, evaluation of residual cancer burden, and long-term outcomes may help define the role of estrogen deprivation in the treatment of HER2-positive early breast cancer,” concluded Dr. Rimawi. ■
Disclosure: Dr. Rimawi reported no potential conflicts of interest.
1. Rimawi MF, Cecchini RS, Rastogi P, et al: A phase III trial evaluating pCR rates with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab with or without estrogen deprivation: NRG Oncology/NSABP B-52. 2016 San Antonio Breast Cancer Symposium. Abstract S3-06. Presented December 8, 2016.
2. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.
Myles Brown, MD
Myles Brown, MD, Director of the Center for Functional Cancer Epigenetics at Dana-Farber Cancer Institute, Boston, suggested the failure of the endocrine therapy to increase the pathologic complete response rates “may be related to the fact that the aromatase inhibitor was...!-->!-->