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2. immune profile of small HER2-positive breast cancers: a secondary analysis from the APT trial.

Author

Barroso-Sousa, R, Barry, W T, Guo, H, Dillon, D, Tan, Y B, Fuhrman, K, Osmani, W, Getz, A, Baltay, M, Dang, C, Yardley, D, Moy, B, Marcom, P K, Mittendorf, E A, Krop, I E, Winer, E P, and Tolaney, S M

Subjects
*HORMONE receptor positive breast cancer, *BREAST cancer, *EPIDERMAL growth factor receptors, *CLINICAL trial registries, *SECONDARY analysis, *BIOMARKERS
Abstract

Background Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics. Patients and methods The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out. Results Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. Conclusion Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome. Clinical trial registration clinicaltrials.gov identifier: NCT00542451. [ABSTRACT FROM AUTHOR]

Published
2019
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3. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

Author

Delaloge, S, Cella, D, Ye, Y, Buyse, M, Chan, A, Barrios, C H, Holmes, F A, Mansi, J, Iwata, H, Ejlertsen, B, Moy, B, Chia, S K L, Gnant, M, Smichkoska, S, Ciceniene, A, Martinez, N, Filipović, S, Ben-Baruch, N E, Joy, A A, and Langkjer, S T

Subjects
*QUALITY of life, *BREAST cancer, *EPIDERMAL growth factor, *ANALYSIS of covariance, *HUMAN comfort
Abstract

Background We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. Patients and methods Women (N   =   2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240  mg/day or placebo for 12  months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy–Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). Results Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N   =   1171; placebo, N   =   1236) and 2427 patients for EQ-5D (neratinib, N   =   1186; placebo, N   =   1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, –2.9 points; EQ-5D index, −0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3–9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. Conclusions Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709. [ABSTRACT FROM AUTHOR]

Published
2019
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4. Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial

Author

Sara A. Hurvitz, Maureen E. Trudeau, William J. Gradishar, Larisa Ryvo, Ming-Shen Dai, Sujith Kalmadi, Cristiano Souza, Eduardo Cronemberger, Suzette Delaloge, Adam Brufsky, Mafalda Oliveira, Vladimir Milovanov, Beverly Moy, Sung Bae Kim, Kiana Keyvanjah, J. Alarcón, Fairooz F. Kabbinavar, Ron Bose, Richard A. Bryce, Cristina Saura, Judith Bebchuk, Barbara Haley, Luciana Landeiro, Institut Català de la Salut, [Hurvitz SA] University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, California, USA. [Saura C, Oliveira M] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Cooperative Group, Barcelona, Spain. [Trudeau ME] Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. [Moy B] Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. [Delaloge S] Gustave Roussy, Villejuif, France, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Oncology, Central Nervous System, Cancer Research, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Neratinib, Other subheadings::Other subheadings::/drug therapy [Other subheadings], ErbB-2, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Cumulative incidence, Other subheadings::/therapeutic use [Other subheadings], Receptor, ErbB‐2, skin and connective tissue diseases, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Hazard ratio, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Metastatic breast cancer, Treatment Outcome, 030220 oncology & carcinogenesis, Quinolines, Female, medicine.symptom, Receptor, medicine.drug, medicine.medical_specialty, Oncology and Carcinogenesis, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Breast Neoplasms, Lapatinib, Asymptomatic, Quimioteràpia combinada, Capecitabine, 03 medical and health sciences, Breast cancer, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Internal medicine, Breast Cancer, medicine, Humans, Oncology & Carcinogenesis, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, medicine.disease, 030104 developmental biology, Central nervous system neoplasms, Mama - Càncer - Tractament, Avaluació de resultats (Assistència sanitària), business
Abstract

Background Neratinib has efficacy in central nervous system (CNS) metastases from HER2‐positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). Materials and Methods NALA was a randomized, active‐controlled trial in patients who received two or more previous HER2‐directed regimens for HER2‐positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression‐free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS‐directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. Conclusion These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2‐positive MBC. Implications for Practice In a subgroup of patients with central nervous system (CNS) metastases from HER2‐positive breast cancer after two or more previous HER2‐directed regimens, the combination of neratinib plus capecitabine was associated with improved progression‐free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2‐positive brain metastases following antibody‐based HER2‐directed therapies., This article reports outcomes among HER2‐positive breast cancer patients with central nervous system metastases at baseline from the phase III NALA trial of neratinib plus capecitabine versus lapatinib plus capecitabine.

Published
2021

5. Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens

Author

Keun Seok Lee, Samuel Guan Wei Ow, J. Alarcón, Mafalda Oliveira, Nina Oestreicher, Larisa Ryvo, Daniele Fagnani, Sung Bae Kim, Cristina Saura, Richard A. Bryce, Judith Bebchuk, Sara A. Hurvitz, Paula Silverman, Ron Bose, Nancy Chan, Suzette Delaloge, Kiana Keyvanjah, Bo Zhang, Sung Chao Chu, Sujith Kalmadi, Beverly Moy, Peter Ang, William J. Gradishar, Ava Kwong, Adam Brufsky, Institut Català de la Salut, [Moy B] Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. [Oliveira M, Saura C] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gradishar W] Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA. [Kim SB] Asan Medical Center, University of Ulsan College of Medicine, Seoul, Kore. [Brufsky A] Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Cancer Research, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Health-related quality of life, Neratinib, Phases of clinical research, Medicaments antineoplàstics - Ús terapèutic, Other subheadings::Other subheadings::/drug therapy [Other subheadings], ErbB-2, Quality of life, Antineoplastic Combined Chemotherapy Protocols, Cancer, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Hazard ratio, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Metastatic breast cancer, Clinical Trial, humanities, Oncology, 6.1 Pharmaceuticals, Quinolines, Female, medicine.drug, Qualitat de vida - Avaluació, Receptor, medicine.medical_specialty, Clinical Trials and Supportive Activities, Clinical Sciences, Oncology and Carcinogenesis, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Breast Neoplasms, Capecitabine, Breast cancer, Clinical Research, Internal medicine, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Breast Cancer, medicine, Humans, Oncology & Carcinogenesis, business.industry, Evaluation of treatments and therapeutic interventions, medicine.disease, HER2-positive, Mama - Càncer - Tractament, Quality of Life, business
Abstract

Health-related quality of life; Metastatic breast cancer; Neratinib Calidad de vida relacionada con la salud; Cáncer de mama metastásico; Neratinib Qualitat de vida relacionada amb la salut; Càncer de mama metastàtic; Neratinib Purpose To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. Methods In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan–Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. Results Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63–1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32–2.23]). Conclusion In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC. This work was supported by Puma Biotechnology Inc., Los Angeles, CA, USA [no grant number is applicable]. Puma Biotechnology Inc. funded the provision of editorial support provided by CMD Consulting and Miller Medical Communications.

Published
2021

6. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

Author

Cristina Saura, Suzette Delaloge, Sung Bae Kim, Mafalda Oliveira, Yen-Shen Lu, Bin Yao, John Crown, Ming-Shen Dai, Hong-Tai Chang, Thomas Yau, Takaaki Fujii, Nala Investigators, Daniele Fagnani, Maureen E. Trudeau, Ming-Feng Hou, William J. Gradishar, Johanna Mattson, Marketa Palacova, Barbara Haley, Masato Takahashi, Beverly Moy, Yu-Min Yeh, Richard Bryce, Kiana Keyvanjah, Miki Yamaguchi, Shang Wen Chen, Judith Bebchuk, Adam Brufsky, Norikazu Masuda, Michelino De Laurentiis, Yin-Hsun Feng, Johnson Lin, Toshimi Takano, Sara A. Hurvitz, Hans Wildiers, Yoon Sim Yap, Institut Català de la Salut, [Saura C, Oliveira M] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOLTI Breast Cancer Cooperative Group, Barcelona, Spain. [Feng YH, Dai MS, Chen SW] Chi Mei Medical Centre, Liouying, Tainan, Taiwan and Tri-Service General Hospital, Taipei, Taiwan. [Hurvitz SA] University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA, Vall d'Hebron Barcelona Hospital Campus, Saura, C., Oliveira, M., Feng, Y. -H., Dai, M. -S., Chen, S. -W., Hurvitz, S. A., Kim, S. -B., Moy, B., Delaloge, S., Gradishar, W., Masuda, N., Palacova, M., Trudeau, M. E., Mattson, J., Yap, Y. S., Hou, M. -F., De Laurentiis, M., Yeh, Y. -M., Chang, H. -T., Yau, T., Wildiers, H., Haley, B., Fagnani, D., Lu, Y. -S., Crown, J., Lin, J., Takahashi, M., Takano, T., Yamaguchi, M., Fujii, T., Yao, B., Bebchuk, J., Keyvanjah, K., Bryce, R., and Brufsky, A.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Receptor, ErbB-2, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Quinoline, Medicaments antineoplàstics - Ús terapèutic, Kaplan-Meier Estimate, THERAPY, Tyrosine-kinase inhibitor, law.invention, chemistry.chemical_compound, ErbB-2, 0302 clinical medicine, Randomized controlled trial, Mama - Càncer, law, Antineoplastic Combined Chemotherapy Protocols, Other subheadings::/therapeutic use [Other subheadings], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Brain Neoplasms, Nausea, ORIGINAL REPORTS, Middle Aged, OPEN-LABEL, Metastatic breast cancer, Progression-Free Survival, 3. Good health, Survival Rate, TRASTUZUMAB EMTANSINE, 030220 oncology & carcinogenesis, Neratinib, Retreatment, Quinolines, Female, Life Sciences & Biomedicine, Breast Neoplasm, medicine.drug, Human, Diarrhea, medicine.medical_specialty, medicine.drug_class, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Lapatinib, Breast Neoplasms, Male, Capecitabine, Brain Neoplasm, 03 medical and health sciences, Internal medicine, Breast Cancer, medicine, Humans, Oncology & Carcinogenesis, Progression-free survival, COMBINATION, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Aged, Science & Technology, Antineoplastic Combined Chemotherapy Protocol, RECEPTOR, business.industry, Otros calificadores::/uso terapéutico [Otros calificadores], Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, 030104 developmental biology, chemistry, Trastuzumab emtansine, Quality of Life, NALA Investigators, business
Abstract

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Published
2020

7. FGFR1 gene amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor positive (HR+) breast cancer

Author

Megan Yuen, Carlos L. Arteaga, Andrzej Niemierko, Luigi Formisano, Neelima Vidula, Jerry Younger, Steven J. Isakoff, Alberto Servetto, Dennis C. Sgroi, Jeffrey Peppercorn, Laura Spring, Joshua Z. Drago, Aditya Bardia, Seth A. Wander, Leif W. Ellisen, Dejan Juric, Beverly Moy, A. John Iafrate, Giuliana Malvarosa, Formisano, L, Drago, Jz, Juric, D, Niemierko, A, Servetto, A, Wander, Sa, Spring, Lm, Vidula, N, Younger, J, Peppercorn, J, Yuen, M, Malvarosa, G, Sgroi, D, Isakoff, Sj, Moy, B, Ellisen, Lw, Iafrate, Aj, Arteaga, Cl, and Bardia, A

Subjects
0301 basic medicine, Cancer Research, medicine.drug_class, medicine.medical_treatment, Palbociclib, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Progesterone receptor, medicine, biological marker circulating tumor DNA cyclin dependent kinase 4 cyclin dependent kinase 6cyclin dependent kinase inhibitor cyclin dependent kinase inhibitor 4cyclin dependent kinase inhibitor 6epidermal growth factor receptor 2estrogen receptor everolimus fibroblast growth factor receptor 1fulvestranthormone receptor letrozole paclitaxel palbociclib phosphatidylinositol 3 kinase progesterone receptor unclassified drug, skin and connective tissue diseases, Everolimus, Fulvestrant, business.industry, medicine.disease, Metastatic breast cancer, stomatognathic diseases, 030104 developmental biology, Oncology, Estrogen, 030220 oncology & carcinogenesis, Cancer research, Hormone therapy, business, medicine.drug
Abstract

Purpose: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined. Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor–positive (HR+)/HER2− MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro. Results: In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2− MBC. In preclinical models, estrogen receptor–positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition. Conclusions: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC.

Published
2019

8. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Beverly Moy, Hiroji Iwata, Gunter von Minckwitz, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Zorica Tomašević, Neelima Denduluri, Robert Šeparović, Erhan Gokmen, Anna Bashford, Manuel Ruiz Borrego, Sung-Bae Kim, Erik Hugger Jakobsen, Audrone Ciceniene, Kenichi Inoue, Friedrich Overkamp, Joan B Heijns, Anne C Armstrong, John S Link, Anil Abraham Joy, Richard Bryce, Alvin Wong, Susan Moran, Bin Yao, Feng Xu, Alan Auerbach, Marc Buyse, Arlene Chan, Vernon Harvey, Rudolf Tomek, Nicholas J. Robert, Ira Gore, John W. Smith, Norikazu Masuda, S. Di Sean Kendall, William Graydon Harker, Katarina Petrakova, Angel Guerrero Zotano, Amparo Ruiz Simon, Zora Neskovic Konstantinovic, Nicholas O. Iannotti, Pierfrancesco Tassone, Gladys I. Rodriguez, Noelia Jáñez Martinez, Carmen Crespo Massieu, Snezana Smickoska, Isil Somali, Ugur Yilmaz, Mirta Garcia Alonso, Adolfo Murias Rosales, Soeren Cold, Ann Soegaard Knoop, Debra Patt, Beth A. Hellerstedt, Serafin Morales Murillo, Ingrid A. Mayer, Julie Ann Means-Powell, Rina Hui, Francis M. Senecal, Richard Hendry De Boer, Zhenzhou Shen, Adam Andrzej Luczak, Joanna W.Y. Chui, Janice Wing-hang Tsang, Istvan Lang, Yoshiaki Rai, Yasuo Hozumi, Albert J. Ten Tije, Manish Bhandari, Cynthia R.C. Osborne, Shoichiro Ohtani, Kenji Higaki, Kenichi Watanabe, Kazunori Taguchi, Masato Takahashi, Sladjana Filipovic, Vincent L. Hansen, Vijayarama Phooshkooru Rao, Manish Gupta, Petar Petrov, Bruno Coudert, Zeljko Vojnovic, Zsofia Polya, Toshiko Miyaki, Naohito Yamamoto, Stephen Brincat, Krzysztof Lesniewski-Kmak, Ewa Chmielowska, Ruemu E. Birhiray, Marc L. Citron, Steven William Papish, William R. Berry, Sven Tyge Langkjer, José Angel Garcia Sáenz, Ana Maria Arance, Noa Efrat, Tomasz Sarosiek, Lukasz Grzeda, Yvonne Manalo, Julie C. Smith, Irfan Vaziri, Tabitha Healey, Yasmin Rahim, Cynthia Luk, Brian Dingle, Sandra Franco, Peter Grundtvig Sorensen, Anjana Anand, Sarah Khan, George Fountzilas, Kenjiro Aogi, Satoru Shimizu, Milada Mikulova, Stanislav Spanik, Robert A. Somer, Patrick J. Flynn, Jermaine Coward, Paul Mainwaring, Guy Jerusalem, Carine Segura-Ojezzar, Christelle Levy, Thierry Delozier, David Khayat, Robert E. Coleman, Martin J. Rolles, Robert Maisano, Mario Nardi, Yoshinori Ito, Perran Fulden Yumuk, Gul Basaran, Nazim Serdar Turhal, Mary J. Wilkinson, Nathan B. Green, Algis P. Sidrys, Sigrun Hallmeyer, Douglas J. Testori, Srikala Sridhar, Jose Chang, Qiang Sun, Carlos Jara-Sanchez, Xabier Rubio, Maria Lomas Garrido, Juan Rafael De La Haba Rodriguez, Antonia Perello Martorell, Antoni Avelia Mestre, Julio Rifa Ferrer, Sonia del Barco Berron, Zsuzsanna Nagy, Maki Tanaka, Young-Hyuck Im, Robert R. Carroll, Laura C. Dickerson, Joseph R. Mace, Ragene Rivera, Leonard M. Klein, Robert Ruxer, Sharon T. Wilks, Dusan Kotasek, Vasil Popov, Violina Taskova, Violetka Marinova-Venkova, Constanta Timcheva, Christine Desbiens, Jean-Pierre Ayoub, Debjani Grenier, Norbert Marschner, Hans Tesch, Hans-Joachim Lueck, Jan Janssen, Ingo Schwaner, Stine Wahlstrom, Eva Harder Brix, Susanne Vallentin, Dan Kristensen, Anna Andreeva, Vesna Glavicic, Isabel Calvo Plaza, Antonio Anton Torres, Corinne Veyret, Jean-Pierre Bergerat, Emmanuelle Bourbouloux, Wendy Ann Ella, Hafiz Algurafi, Anne Robinson, Seung Jin Kim, Tetsuya Taguchi, Elona Juozaityte, Stanley Madretsma, Sandra Radema, Malgorzata Czerniawska-Meier, Wojciech Rogowski, Maria Wagnerova, Donald A. 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Niederman, Theresa Lee, Roland Alexander, Robert Gordon, Antoanet Tomova, Daniel Rauch, Razvan Andrei Popescu, Gustavo Adolfo Rojas, Jaroslav Vanasek, Tanja Neunhoeffer, Jana Barinoff, Gerd Graffunder, Abenhardt Wolfgang, Peter Bojko, Bernhard Heinrich, Albert von der Assen, Bogovic Jurij Antonovic, Lene Adrian, Manuel Ramos Vazquez, Santiago Gonzalez Santiago, Veronique Dieras, Jill Mercia Bishop, Timothy John Perren, Ioannis Varthalitis, Dimitris Mavroudis, Vassilis Georgoulias, Louis W.C. Chow, Chung Cheung Thomas Yau, Raymond Hin-Suen Liang, Béla Pikó, Agnes Wéber, Bella Kaufman, Karen Drumea, Francesco Nuzzo, Andrea De Matteis, Giacomo Carteni, Eriko Tokunaga, Mayumi Ishida, Shinji Ohno, Nobuaki Sato, Katsumasa Kuroi, Reiki Nishimura, Junichiro Watanabe, Yoon Ji Choi, Kyong Hwa Park, Marek Wojtukiewicz, Jacek Jassem, Niklas Loman, Sercan Askoy, Mustafa Kadri Altundag, Pinar Saip, Muhammad Amjad Ali, James Lloyd Wade, Amy Jo Chien, Debra Brandt, Yelena Novik, Chirag Jani, Robert L. Rice, Yousuf A. R Gaffar, Mark R. 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Caton, Mark Urban Rarick, William G. Schimidt, Alison T. Stopeck, Rachel Swart, Maria Regina Carrillo Flores, Carlos A. Alemany, Brennely Lozada, Paul L. Weinstein, Wei Wang, Michael Porubcin, David M. Ellison, George F. Geils, Edgardo Rivera, Mahmoud Charif, Martin, M, Holmes, F, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Chia, S, Mansi, J, Barrios, C, Gnant, M, Tomasevic, Z, Denduluri, N, Separovic, R, Gokmen, E, Bashford, A, Borrego, M, Kim, S, Jakobsen, E, Ciceniene, A, Inoue, K, Overkamp, F, Heijns, J, Armstrong, A, Link, J, Abraham, A, Bryce, J, Wong, A, Moran, S, Yao, B, Xu, F, Auerbach, A, Buyse, M, Chan, A, and Bidoli, P

Subjects
0301 basic medicine, Time Factors, Receptor, ErbB-2, Clinical Trial, Phase III, Receptor, ErbB-2/metabolism, Administration, Oral, Kaplan-Meier Estimate, exteNET, 0302 clinical medicine, Japan, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, pan-HER tyrosine kinase inhibitor, Mastectomy, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Middle Aged, neratinib, trastuzumab, breast cancer, adjuvant, Multicenter Study, Treatment Outcome, Oncology, Antibodies, Monoclonal, Humanized/adverse effects, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Randomized Controlled Trial, Neratinib, Quinolines, Neoplasm Invasiveness/pathology, Female, medicine.drug, Adult, medicine.medical_specialty, Quinolines/administration & dosage, Breast Neoplasms, Placebo, Antibodies, Monoclonal, Humanized, Risk Assessment, Disease-Free Survival, Drug Administration Schedule, Trastuzumab/administration & dosage, 03 medical and health sciences, Breast cancer, Breast Neoplasms/drug therapy, Double-Blind Method, Internal medicine, Journal Article, medicine, Adjuvant therapy, Humans, Comparative Study, Neoplasm Invasiveness, HER2-positive breast cancer, Neoplasm Staging, Proportional Hazards Models, Intention-to-treat analysis, Dose-Response Relationship, Drug, business.industry, medicine.disease, Survival Analysis, Mastectomy/methods, Surgery, Clinical trial, Regimen, 030104 developmental biology, business, Follow-Up Studies
Abstract

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 [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 [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.

Published
2017

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