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Background: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet., Methods: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts., Results: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis., Conclusions: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC., Methods: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR)., Results: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients., Conclusion: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence., (© 2024. The Author(s).)

Purpose: The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study., Methods: Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0-9), intermediate (10-49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher's exact test., Results: Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002-0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2 H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001-0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses., Conclusion: These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18 fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy., Methods: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m 2 , intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing., Findings: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs., Interpretation: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests JMP-G reports consulting roles for Roche, Lilly, Eisai, Daiichi Sankyo, AstraZeneca, Gilead, MSD, and Seattle Genetics and travel expenses from Roche. JC reports consulting roles for Roche, Celgene, Cellestia, AstraZeneca, Biothera Phgroupaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko, Bioasis, and Clovis Oncology; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, and Daiichi Sankyo; research funding to their institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F Hoffman-La Roche, Guardanth health, MSD, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; and intellectual property for Medica Scientia Innovation Research (MEDSIR). MR-B reports membership of a speaker bureau and advisory board for Novartis. MC reports a research grant to their institution from Roche and the role of co-chair of the scientific committee of the International Breast Cancer Study Group. AS reports consulting roles for Roche, AstraZeneca, Seagen, Novartis, and Boehringer Ingelheim; to be part of a speaker bureau for Daiichi Sankyo, Roche, and Novartis; and travel expenses from Pfizer, Novartis, and Eisai. BB reports receiving fees for medical education in a consulting or advisory role with MSD, Roche, Pierre Fabre, Novartis, AstraZeneca, and Seagen; participating in a speakers bureau for Pfizer, Roche, MSD, Palex, Eisai, Daichii Sankyo, AstraZeneca, and Seagen. SE-d-R reports consulting roles for Daiichi Sankyo/AstraZeneca, Seagen, and Pierre Fabre; to be part of a speaker bureau for Daiichi Sankyo/AstraZeneca, Pfizer, Novartis, Seagen; to have received research funding from Roche, Synthon, Byondis, MEDSIR, SOLTI, Zymeworks, and Daiichi Sankyo/AstraZeneca; and travel, accommodation, or expenses from Pfizer, Kern Pharma, and Daiichi Sankyo/AstraZeneca. NR reports research funding from Pfizer; and to be part of speaker bureau for Novartis, Pfizer, Gilead, and Daiichi Sankyo/AstraZeneca. FM reports grants from Roche, Novartis, AstraZeneca, GSK, MSD, Clovis, Vaccibody, Gilead Sciences, and Esai; consulting fees from AstraZeneca, GSK, and Roche; honoraria from AstraZeneca, MSD, Lilly, Pfizer, Novartis, GSK, Clovis, Myriad, Daiichi Sankyo, Seagen, Pierre Fabre, and Agendia; travel support from AstraZeneca, GSK, Pfizer, and Roche; and participation in advisory boards for Palleos and Amgen. AC reports consulting or advisory roles for Daiichi Sankyo/AstraZeneca, Seagen, and Pierre Fabre; being part of a speakers bureau for Daiichi Sankyo/AstraZeneca, Pfizer, Novartis, and Seagen; institutional research funding from Roche, Synthon, Byondis, MEDSIR, SOLTI, Zymeworks, and Daiichi Sankyo/AstraZeneca; and expert testimony and travel or accommodations expenses from Pfizer, Kern Pharma, and Daiichi Sankyo/AstraZeneca. AP reports honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, and Amgen; to have consulting roles for Roche, AstraZeneca, Peptomyc, Novartis, and Daiichi Sankyo; research funding to their institution from Roche, AstraZeneca, Novartis, and Reveal Genomics; to have intellectual property (ERBB2 and HER2DX patents); travel expenses from Daiichi Sankyo; and a share in ownership at Reveal Genomics. PS reports honoraria from Pfizer, AstraZeneca, Novartis, Roche, Merck, and Boehringer Ingelheim; a consulting role in Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and grants to their institution from Roche, Genentech, Oncogenex, and Novartis. SB reports a consulting or advisory board role at Daiichi Sankyo, AstraZeneca, Novartis, and Roche; speaker or conference fees from Daiichi Sankyo, AstraZeneca, Novartis, and Roche; and travel fees from Daiichi Sankyo, AstraZeneca, Novartis, and Roche. SDC reports receiving fees for medical education from Novartis, Pierre Fabre, and IQVIA; institutional grant IG 20774 of Fondazione AIRC per la Ricerca sul Cancro; Cancer Can.Heal European EU4 Health Programme 101080009–European Commission; and serving as an ad hoc medical advisor for MEDSIR. MG reports honoraria from Roche, Novartis, Gilead, and AstraZeneca; travel grants and accommodation from Roche, Pfizer, and AstraZeneca; and an advisory role at Gilead. GA reports honoraria from MEDSIR. AL-C reports leadership roles at Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD; intellectual property for MEDSIR and Initia Research; to have consulting roles for Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, and GSK; to be part of a speakers bureau for Lilly, AstraZeneca, and MSD; research funding from Roche, Foundation Medicine, Pierre Fabre, and Agendia; and travel expenses from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. CP, ES, DA-L, PG, JR-M, LM, and MS-C are employees of MEDSIR. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L., Materials and Methods: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed., Results: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%)., Conclusion: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

Background: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models., Methods: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m 2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies., Results: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes., Conclusions: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%., Trial Registration: NCT01306942, EudraCT 2010-023304-27.

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings., Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants., Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo., Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events., Funding: Wyeth, Pfizer, and Puma Biotechnology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)