Neoadjuvant Endocrine Therapy Appropriate in Select Patients

William J. Gradishar, MD

While not appropriate for all patients with ER-positive breast cancer, neoadjuvant endocrine therapy could play an important role in select groups of women with comorbidities or those with ER-rich/luminal A disease, explained William J. Gradishar MD, during a talk at the Miami Breast Cancer Conference.

"What I would suggest to you is that preoperative endocrine therapy is a reasonable option," explained Gradishar, from the Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center. "I think you have to select carefully. Certainly patients who have very ER-rich tumors, those who are luminal A, certainly patients with comorbidities, older patients who aren't candidates for chemotherapy or surgery, and there are select younger patients who would be suitable candidates for this approach."

In general, patients with ER-positive breast cancer respond less favorably to neoadjuvant therapy compared with other phenotypes. In the large GeparTrio study, the pathological complete response (pCR) rate with chemotherapy in patients with ER-positive disease was 15% compared with up to 57% in triple-negative and 48% in ER/PR-negative.

"The probability of a patient with an ER/PR-positive tumor achieving a path CR is distinctively low. Even in patients with grade 1, who are most likely ER-positive, there's also a low probability with chemotherapy of actually achieving a pCR," Gradishar said. "In this population of patients who are ER-positive, chemotherapy-based regimens may not be particularly effective."

If hormonal therapy is to be used, a decision has to be made between an aromatase inhibitor (AI) and tamoxifen. An examination of key factors showed that treatment with an AI lowered proliferation by 98% compared with 82% with tamoxifen, Gradishar explained. Additionally, there was a 95% reduction in the overexpression of the progesterone receptor with an AI versus 53% with tamoxifen.

The question of which AI to utilize was addressed by the open-label ACOSOG trial, which compared exemestane, letrozole, and anastrozole as neoadjuvant therapy for patients with strongly ER-positive stage II or III breast cancer. The clinical response rate was 60% with exemestane, 72% with letrozole, and 68% with anastrozole. Progression was infrequent in each arm, at an incidence of 5% to 7%.

"There's only a small fraction of patients who have disease progression while they're undergoing preoperative endocrine therapy," Gradishar notes. "So, this should not be a concern."

The question of whether postoperative endocrine therapy or chemotherapy is superior was addressed in a study of 239 postmenopausal women at a median age of 68. This study showed similar outcomes between patients treated with anastrozole or exemestane (n = 121) and those who received doxorubicin plus paclitaxel (n = 118).

"When looking at clinical outcomes and pCR, outcomes looked pretty much the same between endocrine therapy and chemotherapy, which is somewhat surprising," Gradishar said. "Outcomes judged by the rate of breast conserving surgery were a bit higher with endocrine therapy."

In the trial the clinical response rate was 65% with neoadjuvant endocrine therapy versus 64% with chemotherapy. The rate of breast conservation surgery was 33% with endocrine therapy versus 24% with chemotherapy (P = .06).

"Much of the strategies for using either standard cytotoxic chemotherapy or newer endocrine therapy is often in partnership with other targeted therapies," Gradishar said. "If you look at the designs of many of these new trials looking at targeted therapies, many are looking at pairing endocrine therapy with targeted therapies in the preoperative setting."

Early work looking at the combination of letrozole with the mTOR inhibitor everolimus was published in 2009 in the Journal of Clinical Oncology. In this phase II study, the response rate by clinical palpation with the combination was 68.1% compared with 59.1% with letrozole alone (P = .062).

The phase II PALLET study is looking at the combination of letrozole with the CDK 4/6 inhibitor palbociclib as a neoadjuvant therapy for women with postmenopausal ER-positive primary breast cancer. Proliferation by Ki67 and clinical complete response rates are the primary endpoints of the study (NCT02296801).

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