De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study

Abstract

Background In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. Patients and methods PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon’s design, to reject the null hypothesis, at least 8/43 pCR had to be documented. Results Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). Conclusions The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT number 2013-002662-40 ClinicalTrials.gov Identifier NCT02411344

Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

“…1c). Finally, since patients with HER2+/HR+ disease in the PAMELA trial received anti-HER2 therapy in combination with letrozole or tamoxifen, and treatment with letrozole alone for 2 weeks has shown to reduce Ki67 in HER2+/HR+ tumors in the PER-ELISA phase II trial, specially within Luminal A and B disease 10 , we separated and compared the gene expression changes at day 14 in the PAMELA trial of HER2+/HR+/Luminal A or B tumors (n = 38) with HER2+/HR+/HER2-E tumors (n = 38). The analysis revealed a strong correlation (Pearson correlation coefficient = 0.89, p < 0.001) between both gene lists, suggesting that anti-HER2 therapies have a higher impact on molecular tumor changes at day 14 than endocrine therapy ( Supplementary Fig.…”

“…The clinical value of the HER2-E subtype in HER2+ breast cancer is starting to be elucidated. From a therapeutic perspective, the HER2-E subtype has shown, across 14 clinical trials and ∼2,000 patients, higher sensitivity to anti-HER2-based therapies than the non-HER2-E subtypes [7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, not all HER2-E tumors achieve a complete response following anti-HER2-based therapies.…”

Therapeutic significance of hormone receptor positivity in patients with HER-2 positive breast cancer

“…The pCR rate in patients with decreased Ki67 treated with trastuzumab, pertuzumab and letrozole was 20.5% (ref. 31 ).…”

Treatment selection for patients with equivocal HER2 status and in luminal versus HER2 enriched disease

“…Then patients classified as molecular responders (Ki67 relative reduction after 2 weeks >20% from baseline) continued letrozole and started trastuzumab and pertuzumab for 5 cycles achieving pCR in 20.6% of the cases. pCR rate, however, was significantly higher in HER2-enriched vs. other subtypes (45.5% vs. 13.8%) according to PAM50 [24].…”

“…It has been mentioned already that the exquisite sensitivity of HER2-addicted tumours to targeted therapies suggests that a subgroup of patients with early-stage HER2-positive breast cancer, mostly those with the HER2-enriched subtype, might not need chemotherapy if treated with dual HER2 blockade. This option has been tested in a number of neo-adjuvant trials, where the combination of trastuzumab and lapatinib or pertuzumab without cytotoxic therapy has achieved remarkable pCR rates of approximately 20-30% [12,15,[22][23][24][25].…”