Neoadjuvant Estrogen Attack Falters in High-Risk Breast Cancer Patients

Mothaffar F. Rimawi, MD

An attempt to strengthen neoadjuvant treatment of patients with locally advanced HR-positive and HER2-positive breast cancer by adding estrogen deprivation therapy to a standard regimen failed to significantly improve response rates but did illustrate the extensive toxicity of the chemotherapy agents used in this setting.

Those were among the conclusions that researchers reached in the NSABP B-52 trial in which antiestrogen drugs were added to a cocktail of chemotherapy and dual HER2-targeting agents, according to Mothaffar F. Rimawi, MD, who detailed the findings during a press conference at the 2016 San Antonio Breast Cancer Symposium.

The randomized, phase III NRG Oncology study evaluated the TCHP regimen of the chemotherapies docetaxel and carboplatin plus the HER2 inhibitors trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without estrogen deprivation therapy that varied according to menopausal status. All patients went on to receive either a lumpectomy or mastectomy with axillary staging.

Investigators were seeking to evaluate whether an earlier attack on estrogen signaling, which has been implicated as a pathway of resistance in preclinical studies, would result in higher pathologic complete response (pCR) rates than typically achieved with neoadjuvant combination HER2-targeting therapy plus chemotherapy.

The expected rate of pCR in participants not treated with estrogen deprivation therapy was 45%; pCR in the breast and nodes (ypT_0-is ypN₀) was the primary endpoint.

“The general idea was that the estrogen receptor might be causing resistance, so the thought was to pick a regimen that’s quite effective and see if we can add on top of it,” said Rimawi, an associate professor and medical director at the Lester and Sue Smith Breast Center at the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston. “Those patients are going to get endocrine therapy anyway, so we’re not really escalating treatments, we’re just moving up the timeline.”

Although the strategy produced higher response rates among women who received the experimental regimen, the improvement did not reach the level of statistical significance, Rimawi said.

In the breast and nodes, participants who received estrogen deprivation therapy in addition to TCHP (n = 155) demonstrated a 46% pCR rate, compared with a 41% pCR rate for patients (n = 154) in the control group (P = .39). In the subgroup analysis, the experimental combination resulted in pCR rates in the breast and nodes of 46% in premenopausal women and 45% in postmenopausal participants versus 44% and 38%, respectively, for those groups with the control treatment.

A similar pattern was evident for pCR rates in the breast. The pCR rate in the breast was 47% for the overall population of participants who received the experimental therapy versus 44% for women in the control arm (P = .60). For the subgroups, the pCR rates in the breast for premenopausal and postmenopausal women were 49% and 45%, respectively, in the study arm versus 48% and 40%, respectively, for those groups in the control group.

In all, the trial recruited 315 patients with invasive adenocarcinoma of the breast diagnosed by core needle biopsy with HR-positive and HER2-positive status. Patients could be eligible with any size tumor if they were node positive, while those who were node negative were required to have tumors ≥2.0 cm. Data on pCR rates were available for 309 participants.

The patients who enrolled proved to be a high-risk population, Rimawi said. Overall, 46% of participants were aged 49 years or younger, 26% had T3 or greater tumors, and 57% had clinically node-positive disease.

Participants were randomized 1:1 to receive either TCHP or TCHP with estrogen deprivation therapy every 21 days for 6 cycles. For premenopausal patients, the estrogen-targeting therapy consisted of a luteinizing hormone-releasing hormone agonist such as goserelin or an equivalent plus an aromatase inhibitor (AI). Postmenopausal women received an AI.

Rimawi said the trial represented the largest cohort of patients treated with TCHP to date and that adverse events (AEs) were “considerable” in both arms, particularly for gastrointestinal (GI) toxicities. “The overall rate of toxicity was quite high with over 60% of grade 3 and 4 toxicities; however, it was not different between the 2 study arms,” Rimawi remarked.

Frequently reported grade 3-4 toxicities for the experimental arm and the control arm were diarrhea (22% vs 23%), nausea (6% vs 9%), vomiting (5% vs 8%), and dehydration (5% vs 8%). These 4 GI toxicities also were among the most common grade 1 to 2 AEs; these ranged from 76% to 78% for diarrhea to 91% to 95% for dehydration.

Relatively few patients, however, dropped out of the study. “Despite this remarkable toxicity, 90% of the patients in both treatment arms received at least 5 cycles of all 4 drugs and the delivery of the endocrine therapy was also about 90%,” said Rimawi. “It was really quite high.”

Rimawi indicated that changing the chemotherapy paradigm in this patient population is a priority. “Given the toxicity of standard chemotherapy observed on this trial, findings from NSABP B52 argue quite strongly for a tailored de-escalation approach where toxic treatments are omitted or replaced with less toxic ones without compromising outcomes,” he said.

In fact, Rimawi believes the inclusion of chemotherapy in the regimen could have affected the efficacy of the antiestrogen strategy. “Such extensive chemotherapy might have diluted or blunted the effects of estrogen receptor inhibition,” he said. “We believe that if we de-escalate treatment, we could see a higher response to the estrogen receptor.

Such questions should be explored in future clinical trials, along with improved metrics for predicting outcomes for this population in a neoadjuvant setting, Rimawi indicated.

“In tumors that have multiple targets like ER and HER2, the question becomes can we have less extensive chemotherapy in a future trial or even eliminate chemotherapy for a selected group of patients and see if we can maintain a pathologic complete response or some surrogate for outcome and follow those patients make sure the omission of the treatment does not lead to compromised outcomes,” he said.

Rimawi MF, Cecchini RS, Rastogi P, et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S3-06.

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