Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial

 

The Lancet Oncology:  VOLUME 24, ISSUE 3, P273-285, MARCH 2023

 

Background

We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis.

Methods

In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0–1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual.

Findings

Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1–11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3–94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3–98·3), 10-year overall survival was 94·3% (95% CI 91·8–96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6–100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00–1·52]; p=0·047) and recurrence-free interval (1·45 [1·09–1·93]; p=0·011).

Interpretation

Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population.

 

Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: A propensity score-adjusted analysis of a prospective cohort study

 

by RESPECT study group 

The Breast: VOLUME 66, P245-254, DECEMBER 01, 2022

Purpose

To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT).

Methods

Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed.

Results

We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717).

Conclusion

Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy.

 

Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer, followed by T-DM1 after progression

 

by Hans Wildiers, Thomas Meyskens, Sandrine Marréaud, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Bart Meulemans, Berta Sousa, Coralie Poncet, Etienne Brain 

 

The Breast: Published: May 19, 2022

 

Introduction

Older patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC).

Patients and methods

This phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression.

Results

In total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2–32.4) and 28.7% (95% CI 15.8–43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7–58.5) and grade 3 or higher AE occurred in 18 pts (45%).

Conclusions

Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients.

 

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

 

by Pablo Mandó, Sergio G. Rivero, Manglio M. Rizzo, Marina Pinkasz, Estrella M. Levy 

 

The Breast: August 19, 2021

 

The clinical outcome of patients with human epidermal growth factor receptor 2 (HER2) amplified breast carcinoma (BC) has improved with the development of anti-HER2 targeted therapies. However, patients can experience disease recurrence after curative intent and disease progression in the metastatic setting. In the current era of evolving immunotherapy agents, the understanding of the immune response against HER2 tumor cells developed by anti-HER2 antibodies (Abs) is rapidly evolving. Trastuzumab therapy promotes Natural Killer (NK) cell activation in patients with BC overexpressing HER2, indicating that the efficacy of short-term trastuzumab monotherapy, albeit direct inhibition of HER, could also be related with antibody-dependent cell-mediated cytotoxicity (ADCC).

Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial

 

Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial

 

by José Manuel Pérez-García, Geraldine Gebhart, Manuel Ruiz Borrego, Agostina Stradella, Begoña Bermejo, Peter Schmid, Frederik Marmé, Santiago Escrivá-de-Romani, Lourdes Calvo, Nuria Ribelles, Noelia Martinez, Cinta Albacar, Aleix Prat, Florence Dalenc, Khaldoun Kerrou, Marco Colleoni, Noemia Afonso, Serena Di Cosimo, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac, PHERGain steering committee and trial investigators 

 

The Lancet Oncology: VOLUME 22, ISSUE 6, P858-871, JUNE 01, 2021

 

18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy.

Correlation Between Week 24 Trastuzumab-dkst Response and Week 48 Progression-Free Survival: The HERITAGE Trial

 

Correlation Between Week 24 Trastuzumab-dkst Response and Week 48 Progression-Free Survival: The HERITAGE Trial

by Hope S. Rugo, Eduardo J. Pennella, Unmesh Gopalakrishnan, Miguel Hernandez-Bronchud, Jay Herson, Hans Friedrich Koch, Subramanian Loganathan, Sarika Deodhar, Ashwani Marwah, Alexey Manikhas, Igor Bondarenko, Joseph D. Parra, Maria Luisa T. Abesamis-Tiambeng, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Sirshendu Roy, Eduardo Patricio Yanez Ruiz, Abhijit Barve, Cornelius F. Waller 

The Breast: Published: March 31, 2021

Background

Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity.

Methods

HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy.

Results

Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks.

Conclusion

The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

 Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

by Rita De Sanctis, Laura Giordano, Federica D’Antonio, Elisa Agostinetto, Arianna Marinello, Daniela Guiducci, Giovanna Masci, Agnese Losurdo, Monica Zuradelli, Rosalba Torrisi, Armando Santoro 

 

The Breast: VOLUME 57, P80-85, JUNE 01, 2021 (Published: March 17, 2021)

 

Background

Few data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors.

Patients and methods

We retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity.

Results

Within 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups.

Conclusion

Our study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.

Neoadjuvant chemotherapy and HER2 dual blockade including biosimilar trastuzumab (SB3) for HER2-positive early breast cancer: population based real world data from the Danish Breast Cancer Group (DBCG)

 

Neoadjuvant chemotherapy and HER2 dual blockade including biosimilar trastuzumab (SB3) for HER2-positive early breast cancer: population based real world data from the Danish Breast Cancer Group (DBCG)

 

by Tobias Berg, Maj-Britt Jensen, Erik H. Jakobsen, Sami Al-Rawi, Julia Kenholm, Michael Andersson 

 

The Breast: VOLUME 54, P242-247, DECEMBER 01, 2020

 

Highlights

•Real world data on 215 patients with HER2-positive early breast cancer.

•SB3 (biosimilar trastuzumab) and pertuzumab with neoadjuvant chemotherapy.

•pCR in 56% and node conversion in 68% of the patients.

•pCR rate associated with ER-status and malignancy grade.

Abstract

Background

Dual blockade with trastuzumab and pertuzumab combined with neoadjuvant chemotherapy (NACT) has been increasingly used for HER2-positive tumours >2 cm and/or with positive axillary lymph nodes in order to evaluate pathologic response and obtain better surgical management. SB3 is a registered biosimilar trastuzumab approved following a phase III trial demonstrating similar efficacy in the neoadjuvant setting as trastuzumab. However, the study was done without pertuzumab.

Method

The database of the Danish Breast Cancer Group was used to extract data on all patients who started NACT with SB3 and pertuzumab between September 1, 2018 and August 31, 2019. The primary endpoint was pathological complete response (pCR) rate.

Results

In total 215 patients received NACT and dual blockade. The median age was 55 (24–81). NACT used was cyclophosphamide and epirubicin followed by weekly paclitaxel (62% on six cycles, 35% on eight cycles) or other chemotherapy followed by weekly paclitaxel (3%). Overall, 56% of patients achieved pCR. 60 of 88 node-positive patients pre-NACT achieved ypN0(i-) after neoadjuvant treatment. pCR rate was significantly associated with estrogen receptor status and malignancy grade. An association with CEP17/HER2-ratio was assessed.

Conclusion

Real world data on dual blockade with SB3 and pertuzumab in combination with NACT in a nationwide population-based study show a pCR rate comparable to that seen in previous clinical studies.