Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.

Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.

BACKGROUND: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. METHODS: We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. FINDINGS: Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). INTERPRETATION: These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.

Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer.

Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Exons 9 (helical domain) and 20 (kinase domain-KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials.Interactions with clinical, pathological, and biomarker response parameters were examined. A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected(N = 235 P < or = 0.05), but not with treatment-induced changes in Ki67-based proliferation index (N = 418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log-rank P = 0.02) in the P024 trial (N = 153). The favorable prognostic effect was maintained in a multivariable analysis(N = 125) that included the preoperative endocrine prognostic index, an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER, and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9-105 P = 0.01). PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor-positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained.

The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics.

PURPOSE: To investigate the safety and pharmacokinetics (PK) of combined treatment with letrozole and the oral mTOR inhibitor RAD001 in patients with metastatic breast cancer stable or progressing after > or = 4 months on letrozole alone. METHODS: Eighteen patients received letrozole (2.5 mg/day) and RAD001 at 5 mg/day (cohort 1) or 10 mg/day (cohort 2). In the absence of DLT in cohort 1, cohort 2 was expanded to 12 patients to obtain additional safety and PK data. RESULTS: Most common adverse events were stomatitis (50.0% of patients), fatigue (44.4%), anorexia and/or decreased appetite (44.4%), diarrhoea (38.9%), headache (33.3%) and rash (33.3%). There was 1 DLT, a grade 3 thrombocytopaenia in cohort 2. No clinically relevant PK interaction was detected. Seven patients received the combination therapy for >6 months. One patient had a complete response, and one had a 28% reduction in liver metastases, both in cohort 2. CONCLUSION: Daily therapy with RAD001 plus letrozole is promising: the results suggest anti-tumour activity with no PK interactions. The overall safety profile of the combination is consistent with that expected for RAD001 monotherapy. A daily dose of RAD001 10mg is recommended for further trials.

Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy.

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers' increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.

Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01).

PURPOSE: To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy. PATIENTS AND METHODS: The Herceptin Adjuvant (HERA) trial is a three-arm, randomized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2) -positive early-stage breast cancer. Cardiac function was closely monitored. Eligible patients had left ventricular ejection fraction (LVEF) ≥ 55% at study entry following neoadjuvant chemotherapy with or without radiotherapy. This 8-year median follow-up analysis considered patients randomly assigned to 2 years or 1 year of trastuzumab or observation. RESULTS: The as-treated safety population for 2 years of trastuzumab (n = 1,673), 1 year of trastuzumab (n = 1,682), and observation (n = 1,744) is reported. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of patients in the 2-year arm and 5.2% of patients in the 1-year arm. Cardiac death, severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. The incidence of severe CHF (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant LVEF decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe CHF was the same for 2-year and 1-year trastuzumab. Of patients with confirmed LVEF decrease receiving 2-year trastuzumab, 87.5% reached acute recovery. Of patients with confirmed LVEF decrease receiving 1-year trastuzumab, 81.2% reached acute recovery. CONCLUSION: Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy, and cardiac events were reversible in the vast majority of patients.

Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.

PURPOSE: Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001). PATIENTS AND METHODS: Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry. RESULTS: Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, alpha = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo. CONCLUSION: Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.