De-escalated, Chemo-Free Neoadjuvant Path Viable in HER2+/HR+ Breast Cancer

A de-escalated, chemotherapy-free neoadjuvant regimen of letrozole plus dual HER2 blockade showed promise in patients with HER2+/HR+ breast cancer who first achieved a molecular response to 2 weeks of letrozole, according to findings from the phase II PerElisa study presented at the 2018 ASCO Annual Meeting.

Between January 2014 and July 2017 64 patients across 8 institutions were enrolled in PerElisa. Patients received 2 weeks of letrozole followed by a core biopsy for molecular response assessment. The study defined molecular response as Ki67 reduction of >20% from baseline. Among evaluable patients, there were 44 patients with a molecular response and 17 patients who did not reach a molecular response.

Nine (20.5%) of the 44 molecular responders then achieved a pathologic complete response (pCR) to the de-escalated, chemotherapy-free regimen of letrozole plus trastuzumab (Herceptin) and pertuzumab (Perjeta), meeting the primary endpoint of the study. Also in these patients, the breast objective response rate was 74%. Additionally, the rate of breast conserving surgery (BCS) was 65.9% and the rate of conversion from mastectomy to BCS was 54.5%.

Additionally, PAM50 analysis of intrinsic biological subtypes showed that patients in the HER2-enriched subtype were the most likely to benefit from the de-escalated approach, as the pCR rate to the chemotherapy-free regimen was 45% among the molecular responders in this group.

“The PerElisa study met its primary endpoint—a chemotherapy-free-regimen with letrozole plus trastuzumab and pertuzumab warrants further investigation in HER2+/HR+ molecular responding patients,” lead author Valentina Guarneri, MD, PhD, associate professor of Oncology at the University of Padua, and attending physician at the Division of Medical Oncology 2 at the Istituto Oncologico Veneto in Italy, said when presenting the data at ASCO.

“Short-term neoadjuvant letrozole can guide treatment selection on the basis of the modulation of Ki67,” added Guarneri.

Among molecular nonresponders, the pCR was 81.3%, the breast object response rate was 94%, the BCS rate was 62.5%, and the rate of conversion from mastectomy to BCS was 57%.

“Patients with no molecular response after short-term letrozole are ideal candidates for chemotherapy plus dual anti-HER2 blockade,” said Guarneri.

Per the study design, the 44 patients with a molecular response to 2 weeks of neoadjuvant letrozole continued with letrozole at 2.5 mg continuous daily dosing and started trastuzumab at an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks for 5 cycles, along with pertuzumab at an 840-mg loading dose followed by 420 mg every 3 weeks for 5 cycles.

The 17 molecular nonresponders discontinued letrozole and started paclitaxel at 80 mg/m² weekly for 13 weeks, along with the same trastuzumab and pertuzumab regimens as in the cohort of molecular responders.

For both cohorts, patients underwent surgery within 3 weeks of the last treatment administration. Treatment options after surgery included radiotherapy per local standards, trastuzumab for up to 1 year, hormonal therapy for at least 5 years, and additional chemotherapy at the treating physician’s discretion.

All 44 responders completed the assigned treatment and underwent surgery. Of the 17 non-responders, 16 completed their subsequent treatment and had surgery. The other patient discontinued treatment due to a cardiac adverse event (AE).

Baseline characteristics were well balanced between the 2 arms. Among all 61 evaluable patients, the median age was 64 (range, 49-83), 67% of patients had stage IIA disease, 26% had stage IIB, and 6% had stage IIIA/B. The vast majority (92%) of patients had ductal carcinoma, with the remaining (8%) of patients having lobular carcinoma or another histology. Twenty-four percent of patients had grade 2 disease and 76% had grade 3.

The median ER expression was 90% among responders and 60% among nonresponders. The median PgR expression was 20% versus 0%, respectively.

“A higher ER (P = .014) and PgR (P = .013) expression were significantly associated with the probability of having a molecular response after [the initial] 2 weeks of letrozole,” said Guarneri.

There were no grade 4 AEs. Grade 3 AEs occurring among molecular responders included hypertension (2.3%), musculoskeletal symptoms (2.3%), and allergic reaction (2.3%). Among molecular nonresponders, grade 3 AEs included neuropathy (11.7%), skin reactions (5.8%), neutropenia (5.8%), heart failure (5.8%), abdominal pain (5.8%), GGT increase (5.8%).

Tumor infiltrating lymphocytes (TILs), PIK3CA mutation status, and intrinsic subtype were “evaluated as potential predictors of molecular response and pCR,” said Guarneri.

“We did not find any significant correlation between TILs and PIK3CA status with molecular response or pCR,” noted Guarneri.

However, there was a significant correlation (P = .001) between molecular response after 2 weeks of letrozole and intrinsic subtype per PAM50 analysis. The molecular response rate was 100% among the 7 luminal A patients; 90% among the 20 luminal B patients; 48% among the 23 HER2-enriched patients; 0% among the 2 basal-like patients; and 100% among the 4 normal-like patients.

Guarneri added, “Among molecular responders the pCR rate in the HER2-enriched subtype was 45%, which was significantly higher as compared to the other subtypes (P = .032). The pCR rates were 14%, 17%, and 0% among the molecular responders in the luminal A, luminal B, and normal-like subgroups, respectively.”

Going forward, “Centralized Ki67 evaluation is ongoing. A definitive standardized Ki67 assessment is eagerly needed,” concluded Guarneri.

Guarneri V, Dieci MV, Bisagni G, et al. De-escalated treatment with trastuzumab-pertuzumab-letrozole in patients with HR+/HER2+ operable breast cancer with Ki67 response after 2 weeks letrozole: Final results of the PerELISA neoadjuvant study. J Clin Oncol. 2018;36 (suppl; abstr 507).