Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study

L. Gianni, G. Bisagni, M. Colleoni, L. Del Mastro, C. Zamagni, M. Mansutti, M. Zambetti, A. Frassoldati, R. De Fato, P. Valagussa, G. Viale

Research output: Contribution to journalArticle

Abstract

Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p
Original languageEnglish
Pages (from-to)249-256
Number of pages8
JournalThe Lancet Oncology
Volume19
Issue number2
DOIs
Publication statusPublished - 2018

Fingerprint

Neoadjuvant Therapy
Breast Neoplasms
Safety
palbociclib
fulvestrant
Trastuzumab
pertuzumab
Aromatase Inhibitors
Estrogen Receptors
Italy
Therapeutics
Pharmacology
Apoptosis

Keywords

  • alanine aminotransferase
  • fulvestrant
  • Ki 67 antigen
  • palbociclib
  • pertuzumab
  • retinoblastoma protein
  • retinoblastoma protein 1
  • trastuzumab
  • unclassified drug
  • antineoplastic agent
  • epidermal growth factor receptor 2
  • estrogen receptor
  • monoclonal antibody
  • piperazine derivative
  • pyridine derivative
  • adult
  • aged
  • alanine aminotransferase blood level
  • allergic reaction
  • apoptosis
  • Article
  • axillary lymph node
  • breast surgery
  • cancer grading
  • clinical article
  • cohort analysis
  • diarrhea
  • drug safety
  • drug toxicity
  • drug withdrawal
  • estrogen receptor positive breast cancer
  • exploratory research
  • female
  • human
  • human epidermal growth factor receptor 2 positive breast cancer
  • human tissue
  • Italy
  • loading drug dose
  • multicenter study
  • multiple cycle treatment
  • neoadjuvant therapy
  • neutropenia
  • open study
  • outcome assessment
  • phase 2 clinical trial
  • priority journal
  • protein expression
  • protein targeting
  • repeated drug dose
  • side effect
  • stomatitis
  • WERI-Rb-1 cell line
  • breast tumor
  • clinical trial
  • disease free survival
  • intramuscular drug administration
  • intravenous drug administration
  • Kaplan Meier method
  • middle aged
  • mortality
  • oral drug administration
  • pathology
  • procedures
  • prognosis
  • proportional hazards model
  • response evaluation criteria in solid tumors
  • survival analysis
  • treatment outcome
  • Administration, Oral
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Breast Neoplasms
  • Disease-Free Survival
  • Female
  • Fulvestrant
  • Humans
  • Infusions, Intravenous
  • Injections, Intramuscular
  • Kaplan-Meier Estimate
  • Middle Aged
  • Neoadjuvant Therapy
  • Piperazines
  • Prognosis
  • Proportional Hazards Models
  • Pyridines
  • Receptor, ErbB-2
  • Receptors, Estrogen
  • Response Evaluation Criteria in Solid Tumors
  • Survival Analysis
  • Trastuzumab
  • Treatment Outcome

Cite this

Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. / Gianni, L.; Bisagni, G.; Colleoni, M.; Del Mastro, L.; Zamagni, C.; Mansutti, M.; Zambetti, M.; Frassoldati, A.; De Fato, R.; Valagussa, P.; Viale, G.

In: The Lancet Oncology, Vol. 19, No. 2, 2018, p. 249-256.

Research output: Contribution to journalArticle

@article{0ced061037f44122b24cd6f4a5db183b,
title = "Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study",
abstract = "Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21{\%} of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p",
keywords = "alanine aminotransferase, fulvestrant, Ki 67 antigen, palbociclib, pertuzumab, retinoblastoma protein, retinoblastoma protein 1, trastuzumab, unclassified drug, antineoplastic agent, epidermal growth factor receptor 2, estrogen receptor, monoclonal antibody, piperazine derivative, pyridine derivative, adult, aged, alanine aminotransferase blood level, allergic reaction, apoptosis, Article, axillary lymph node, breast surgery, cancer grading, clinical article, cohort analysis, diarrhea, drug safety, drug toxicity, drug withdrawal, estrogen receptor positive breast cancer, exploratory research, female, human, human epidermal growth factor receptor 2 positive breast cancer, human tissue, Italy, loading drug dose, multicenter study, multiple cycle treatment, neoadjuvant therapy, neutropenia, open study, outcome assessment, phase 2 clinical trial, priority journal, protein expression, protein targeting, repeated drug dose, side effect, stomatitis, WERI-Rb-1 cell line, breast tumor, clinical trial, disease free survival, intramuscular drug administration, intravenous drug administration, Kaplan Meier method, middle aged, mortality, oral drug administration, pathology, procedures, prognosis, proportional hazards model, response evaluation criteria in solid tumors, survival analysis, treatment outcome, Administration, Oral, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Disease-Free Survival, Female, Fulvestrant, Humans, Infusions, Intravenous, Injections, Intramuscular, Kaplan-Meier Estimate, Middle Aged, Neoadjuvant Therapy, Piperazines, Prognosis, Proportional Hazards Models, Pyridines, Receptor, ErbB-2, Receptors, Estrogen, Response Evaluation Criteria in Solid Tumors, Survival Analysis, Trastuzumab, Treatment Outcome",
author = "L. Gianni and G. Bisagni and M. Colleoni and {Del Mastro}, L. and C. Zamagni and M. Mansutti and M. Zambetti and A. Frassoldati and {De Fato}, R. and P. Valagussa and G. Viale",
note = "Cited By :20 Export Date: 5 February 2019 CODEN: LOANB Correspondence Address: Gianni, L.; San Raffaele Scientific InstituteItaly; email: gianni.luca@hsr.it Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; fulvestrant, 129453-61-8; palbociclib, 571190-30-2, 827022-33-3; trastuzumab, 180288-69-1, 1446410-98-5; epidermal growth factor receptor 2, 137632-09-8; Antibodies, Monoclonal, Humanized; Fulvestrant; palbociclib; pertuzumab; Piperazines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Trastuzumab References: Gianni, L., Eiermann, W., Semiglazov, V., 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 (2014) Lancet Oncol, 15, pp. 640-647; Baselga, J., Bradbury, I., Eidtmann, H., Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial (2012) Lancet, 379, pp. 633-640; Gianni, L., Pienkowski, T., Im, Y.-H., Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial (2012) Lancet Oncol, 13, pp. 25-32; Cortazar, P., Zhang, L., Untch, M., Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis (2014) Lancet, 384, pp. 164-172; Bianchini, G., Prat, A., Pickl, M., Response to neoadjuvant trastuzumab and chemotherapy in ER+ and ER- HER2-positive breast cancers: gene expression analysis (2011) Proc Am Soc Clin Oncol, 29. , abstr 529; Leary, A.F., Drury, S., Detre, S., Lapatinib restores hormone sensitivity with differential effects on estrogen receptor signaling in cell models of human epidermal growth factor receptor 2-negative breast cancer with acquired endocrine resistance (2010) Clin Cancer Res, 16, pp. 1486-1497; Kaufman, B., Mackey, J.R., Clemens, M.R., Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study (2009) J Clin Oncol, 27, pp. 5529-5537; Johnston, S., Pippen, J., Jr, Pivot, X., Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer (2009) J Clin Oncol, 27, pp. 5538-5546; Baselga, J., Campone, M., Piccart, M., Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (2012) N Engl J Med, 366, pp. 520-529; Cristofanilli, M., Turner, N.C., Bondarenko, I., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial (2016) Lancet Oncol, 17, pp. 425-439; Ma, C.X., Gao, F., Luo, J., NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer (2017) Clin Cancer Res, 23, pp. 4055-4065; Finn, R.S., Crown, J.P., Ettl, J., Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO (2016) Breast Cancer Res, 18, pp. 67-81; Sledge, G.W., Jr, Toi, M., Neven, P., MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy (2017) J Clin Oncol, 35, pp. 2875-2884; Hortobagyi, G., Stemmer, S.M., Burris, H.A., Ribociclib as first-line therapy for HR-positive, advanced breast cancer (2016) N Engl J Med, 375, pp. 1738-1748; Finn, R.S., Dering, J., Conklin, D., PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro (2009) Breast Cancer Res, 11, p. R77; Sheri, A., Dowsett, M., Developments in Ki67 and other biomarkers for treatment decision making in breast cancer (2012) Ann Oncol, 23, pp. x219-x227; Dowsett, M., Nielsen, T.O., A'Hern, R., Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group (2011) J Natl Cancer Inst, 103, pp. 1656-1664; Pathmanathan, N., Balleine, R.L., Ki 67 and proliferation in breast cancer (2013) J Clin Pathol, 66, pp. 512-516; Loibl, S., Gianni, L., HER2-positive breast cancer (2017) Lancet, 389, pp. 2415-2429; Ferrari, A., Vincent-Salomon, A., Pivot, X., A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers (2016) Nat Commun, 7, p. 12222; Carey, L.A., Berry, D.A., Cirrincione, C.T., Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib (2015) J Clin Oncol, 34, pp. 542-549; Arpino, G., Gurtierrez, C., Weiss, H., Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy (2007) J Natl Cancer Inst, 99, pp. 694-705; Rimawi, M.F., Wiechmann, L.S., Wang, Y.C., Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts (2011) Clin Cancer Res, 17, pp. 1351-1361; Arpino, G., Ferrero, J.-M., de la Haba-Rodriguez, J., Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (2017) Cancer Res, 77 (4). , abstr S3-04; Rimawi, M.F., Mayer, I.A., Forero, A., Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006 (2013) J Clin Oncol, 31, pp. 1726-1731; Goel, S., Wang, Q., Watt, A.C., Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors (2016) Cancer Cell, 29, pp. 255-269; Dowsett, M., Smith, I., Robertson, J., Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer (2011) J Natl Cancer Inst Monogr, 43, pp. 120-123",
year = "2018",
doi = "10.1016/S1470-2045(18)30001-9",
language = "English",
volume = "19",
pages = "249--256",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "2",

}

TY - JOUR

T1 - Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study

AU - Gianni, L.

AU - Bisagni, G.

AU - Colleoni, M.

AU - Del Mastro, L.

AU - Zamagni, C.

AU - Mansutti, M.

AU - Zambetti, M.

AU - Frassoldati, A.

AU - De Fato, R.

AU - Valagussa, P.

AU - Viale, G.

N1 - Cited By :20 Export Date: 5 February 2019 CODEN: LOANB Correspondence Address: Gianni, L.; San Raffaele Scientific InstituteItaly; email: gianni.luca@hsr.it Chemicals/CAS: alanine aminotransferase, 9000-86-6, 9014-30-6; fulvestrant, 129453-61-8; palbociclib, 571190-30-2, 827022-33-3; trastuzumab, 180288-69-1, 1446410-98-5; epidermal growth factor receptor 2, 137632-09-8; Antibodies, Monoclonal, Humanized; Fulvestrant; palbociclib; pertuzumab; Piperazines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Trastuzumab References: Gianni, L., Eiermann, W., Semiglazov, V., 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 (2014) Lancet Oncol, 15, pp. 640-647; Baselga, J., Bradbury, I., Eidtmann, H., Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial (2012) Lancet, 379, pp. 633-640; Gianni, L., Pienkowski, T., Im, Y.-H., Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial (2012) Lancet Oncol, 13, pp. 25-32; Cortazar, P., Zhang, L., Untch, M., Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis (2014) Lancet, 384, pp. 164-172; Bianchini, G., Prat, A., Pickl, M., Response to neoadjuvant trastuzumab and chemotherapy in ER+ and ER- HER2-positive breast cancers: gene expression analysis (2011) Proc Am Soc Clin Oncol, 29. , abstr 529; Leary, A.F., Drury, S., Detre, S., Lapatinib restores hormone sensitivity with differential effects on estrogen receptor signaling in cell models of human epidermal growth factor receptor 2-negative breast cancer with acquired endocrine resistance (2010) Clin Cancer Res, 16, pp. 1486-1497; Kaufman, B., Mackey, J.R., Clemens, M.R., Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study (2009) J Clin Oncol, 27, pp. 5529-5537; Johnston, S., Pippen, J., Jr, Pivot, X., Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer (2009) J Clin Oncol, 27, pp. 5538-5546; Baselga, J., Campone, M., Piccart, M., Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (2012) N Engl J Med, 366, pp. 520-529; Cristofanilli, M., Turner, N.C., Bondarenko, I., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial (2016) Lancet Oncol, 17, pp. 425-439; Ma, C.X., Gao, F., Luo, J., NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer (2017) Clin Cancer Res, 23, pp. 4055-4065; Finn, R.S., Crown, J.P., Ettl, J., Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO (2016) Breast Cancer Res, 18, pp. 67-81; Sledge, G.W., Jr, Toi, M., Neven, P., MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy (2017) J Clin Oncol, 35, pp. 2875-2884; Hortobagyi, G., Stemmer, S.M., Burris, H.A., Ribociclib as first-line therapy for HR-positive, advanced breast cancer (2016) N Engl J Med, 375, pp. 1738-1748; Finn, R.S., Dering, J., Conklin, D., PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro (2009) Breast Cancer Res, 11, p. R77; Sheri, A., Dowsett, M., Developments in Ki67 and other biomarkers for treatment decision making in breast cancer (2012) Ann Oncol, 23, pp. x219-x227; Dowsett, M., Nielsen, T.O., A'Hern, R., Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group (2011) J Natl Cancer Inst, 103, pp. 1656-1664; Pathmanathan, N., Balleine, R.L., Ki 67 and proliferation in breast cancer (2013) J Clin Pathol, 66, pp. 512-516; Loibl, S., Gianni, L., HER2-positive breast cancer (2017) Lancet, 389, pp. 2415-2429; Ferrari, A., Vincent-Salomon, A., Pivot, X., A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers (2016) Nat Commun, 7, p. 12222; Carey, L.A., Berry, D.A., Cirrincione, C.T., Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib (2015) J Clin Oncol, 34, pp. 542-549; Arpino, G., Gurtierrez, C., Weiss, H., Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy (2007) J Natl Cancer Inst, 99, pp. 694-705; Rimawi, M.F., Wiechmann, L.S., Wang, Y.C., Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts (2011) Clin Cancer Res, 17, pp. 1351-1361; Arpino, G., Ferrero, J.-M., de la Haba-Rodriguez, J., Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (2017) Cancer Res, 77 (4). , abstr S3-04; Rimawi, M.F., Mayer, I.A., Forero, A., Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006 (2013) J Clin Oncol, 31, pp. 1726-1731; Goel, S., Wang, Q., Watt, A.C., Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors (2016) Cancer Cell, 29, pp. 255-269; Dowsett, M., Smith, I., Robertson, J., Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer (2011) J Natl Cancer Inst Monogr, 43, pp. 120-123

PY - 2018

Y1 - 2018

N2 - Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p

AB - Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p

KW - alanine aminotransferase

KW - fulvestrant

KW - Ki 67 antigen

KW - palbociclib

KW - pertuzumab

KW - retinoblastoma protein

KW - retinoblastoma protein 1

KW - trastuzumab

KW - unclassified drug

KW - antineoplastic agent

KW - epidermal growth factor receptor 2

KW - estrogen receptor

KW - monoclonal antibody

KW - piperazine derivative

KW - pyridine derivative

KW - adult

KW - aged

KW - alanine aminotransferase blood level

KW - allergic reaction

KW - apoptosis

KW - Article

KW - axillary lymph node

KW - breast surgery

KW - cancer grading

KW - clinical article

KW - cohort analysis

KW - diarrhea

KW - drug safety

KW - drug toxicity

KW - drug withdrawal

KW - estrogen receptor positive breast cancer

KW - exploratory research

KW - female

KW - human

KW - human epidermal growth factor receptor 2 positive breast cancer

KW - human tissue

KW - Italy

KW - loading drug dose

KW - multicenter study

KW - multiple cycle treatment

KW - neoadjuvant therapy

KW - neutropenia

KW - open study

KW - outcome assessment

KW - phase 2 clinical trial

KW - priority journal

KW - protein expression

KW - protein targeting

KW - repeated drug dose

KW - side effect

KW - stomatitis

KW - WERI-Rb-1 cell line

KW - breast tumor

KW - clinical trial

KW - disease free survival

KW - intramuscular drug administration

KW - intravenous drug administration

KW - Kaplan Meier method

KW - middle aged

KW - mortality

KW - oral drug administration

KW - pathology

KW - procedures

KW - prognosis

KW - proportional hazards model

KW - response evaluation criteria in solid tumors

KW - survival analysis

KW - treatment outcome

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Breast Neoplasms

KW - Disease-Free Survival

KW - Female

KW - Fulvestrant

KW - Humans

KW - Infusions, Intravenous

KW - Injections, Intramuscular

KW - Kaplan-Meier Estimate

KW - Middle Aged

KW - Neoadjuvant Therapy

KW - Piperazines

KW - Prognosis

KW - Proportional Hazards Models

KW - Pyridines

KW - Receptor, ErbB-2

KW - Receptors, Estrogen

KW - Response Evaluation Criteria in Solid Tumors

KW - Survival Analysis

KW - Trastuzumab

KW - Treatment Outcome

U2 - 10.1016/S1470-2045(18)30001-9

DO - 10.1016/S1470-2045(18)30001-9

M3 - Article

VL - 19

SP - 249

EP - 256

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 2

ER -