Top

Published in:

01-10-2020 | Breast Cancer | Epidemiology

The efficacy of first-line chemotherapy in endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer

Authors: Sudpreeda Chainitikun, James P. Long, Ruben Rodriguez-Bautista, Toshiaki Iwase, Debu Tripathy, Takeo Fujii, Naoto T. Ueno

Published in: Breast Cancer Research and Treatment | Issue 3/2020

Abstract

Purpose

Combinations of endocrine therapy (ET) and targeted therapy (CDK4/6 or mTOR inhibitors) are standard of care for HR+/HER2− metastatic breast cancer (MBC). When ET is not effective, chemotherapy is commonly used. However, clinical outcomes of chemotherapy in the endocrine-resistant setting are limited. The purpose of this study was to identify predictive factors and the compare efficacies of chemotherapy agents in endocrine-resistant MBC.

Methods

We conducted a retrospective study of patients with HR+/HER2− MBC who received chemotherapy after progression on ET with or without targeted therapy at MD Anderson Cancer Center from 1999 to 2017. We collected baseline clinicopathological and all treatment data. Primary endpoint was time to treatment failure (TTF) of first-line chemotherapy for MBC.

Results

For the 1258 patients analyzed, mean age was 55.3 years (range 21–91). Previous treatment with targeted therapy was recorded for 390 patients (31%): 264 with CDK4/6 inhibitor, 205 with mTOR inhibitor, and 79 treated with both. The most frequent chemotherapy agents were capecitabine (48.9%) and taxanes (28.6%). After adjustment for all factors in a multivariate model, previous treatment with a CDK4/6 inhibitor had the strongest negative effect on TTF regardless of ET duration (hazard ratio [HR] 1.84; 95%CI 1.49–2.27; p < 0.001). Conversely, capecitabine had significantly longer median TTF than taxanes regardless of whether patients had prior exposure to taxanes in primary setting (6.1 vs 4.9 months; HR 0.64; 95%CI 0.55–0.75; p < 0.001).

Conclusions

Previous exposure to CDK4/6 inhibitor had a negative predictive effect for the efficacy of chemotherapy. Capecitabine had the best efficacy against endocrine-resistant breast cancer.

Available only for authorised users

National Comprehensive Cancer Network (2020) NCCN clinical practice guidelines in oncology: breast cancer (version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 3 Jan 2020

Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortes J, Curigliano G, Dieras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP (2018) 4th ESO-ESMO International consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol 29(8):1634–1657. https://doi.org/10.1093/annonc/mdy192CrossRefPubMed

Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, Fallowfield L, Fowble B, Ingle JN, Jahanzeb M, Johnston SR, Korde LA, Khatcheressian JL, Mehta RS, Muss HB, Burstein HJ (2016) Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 34(25):3069–3103. https://doi.org/10.1200/JCO.2016.67.1487CrossRefPubMed

Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D (2019) Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med 381(4):307–316. https://doi.org/10.1056/NEJMoa1903765CrossRefPubMed

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke E-M, Conte P, Lu Y, Barriga S, Hurt K, Frenzel M, Johnston S, Llombart-Cussac A (2019) The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, erbb2-negative breast cancer that progressed on endocrine therapy MONARCH 2: a randomized clinical trial. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2019.4782CrossRefPubMedPubMedCentral

Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529. https://doi.org/10.1056/NEJMoa1109653CrossRefPubMed

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A (2017) MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35(25):2875–2884. https://doi.org/10.1200/JCO.2017.73.7585CrossRefPubMed

Prat A, Fan C, Fernandez A, Hoadley KA, Martinello R, Vidal M, Viladot M, Pineda E, Arance A, Munoz M, Pare L, Cheang MC, Adamo B, Perou CM (2015) Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med 13:303. https://doi.org/10.1186/s12916-015-0540-zCrossRefPubMedPubMedCentral

Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E (2012) Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 48(18):3342–3354. https://doi.org/10.1016/j.ejca.2012.05.023CrossRefPubMed

10.

Zhu Y, Liu Y, Zhang C, Chu J, Wu Y, Li Y, Liu J, Li Q, Li S, Shi Q, Jin L, Zhao J, Yin D, Efroni S, Su F, Yao H, Song E, Liu Q (2018) Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1. Nat Commun 9(1):1595. https://doi.org/10.1038/s41467-018-03951-0CrossRefPubMedPubMedCentral

11.

Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC, American Society of Clinical Oncology, Oncology College of American Pathologists (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134(7):e48–e72. https://doi.org/10.1043/1543-2165-134.7.e48CrossRef

12.

Harbeck N, Gnant M (2017) Breast cancer. Lancet (London, England) 389(10074):1134–1150. https://doi.org/10.1016/s0140-6736(16)31891-8CrossRef

13.

Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Andre F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M (2018) Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379(20):1926–1936. https://doi.org/10.1056/NEJMoa1810527CrossRefPubMed

14.

Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D (2016) 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. Lancet Oncol 17(4):425–439. https://doi.org/10.1016/S1470-2045(15)00613-0CrossRefPubMed

15.

Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS (2011) Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol 29(34):4498–4504. https://doi.org/10.1200/JCO.2010.33.9101CrossRefPubMed

16.

Harbeck N, Saupe S, Jager E, Schmidt M, Kreienberg R, Muller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Luck HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE, Investigators P (2017) A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat 161(1):63–72. https://doi.org/10.1007/s10549-016-4033-3CrossRefPubMed

17.

Talbot DC, Moiseyenko V, Van Belle S, O'Reilly SM, Alba Conejo E, Ackland S, Eisenberg P, Melnychuk D, Pienkowski T, Burger HU, Laws S, Osterwalder B (2002) Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 86(9):1367–1372. https://doi.org/10.1038/sj.bjc.6600261CrossRefPubMedPubMedCentral

18.

Oshaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger HU, Laws S (2001) Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12(9):1247–1254. https://doi.org/10.1023/a:1012281104865CrossRefPubMed

19.

Pazdur R (2008) Endpoints for assessing drug activity in clinical trials. Oncologist 13(Suppl 2):19–21. https://doi.org/10.1634/theoncologist.13-S2-19CrossRefPubMed

Title: The efficacy of first-line chemotherapy in endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer
Authors: Sudpreeda Chainitikun
James P. Long
Ruben Rodriguez-Bautista
Toshiaki Iwase
Debu Tripathy
Takeo Fujii
Naoto T. Ueno
Publication date: 01-10-2020
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Targeted Therapy
Cytostatic Therapy
mTOR-Inhibitors
Fulvestrant
Published in: Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05837-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2020

Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy

Identifying germline APOBEC3B deletion and immune phenotype in Korean patients with operable breast cancer

The histopathological and molecular features of breast carcinoma with tumour budding—a systematic review and meta-analysis

Radial scars and complex sclerosing lesions on core needle biopsy of the breast: upgrade rates and long-term outcomes

Differential expression and prognostic relevance of autophagy-related markers ATG4B, GABARAP, and LC3B in breast cancer

Sarcoma of the breast: breast cancer history as etiologic and prognostic factor—A population-based case–control study

Keynote webinar | Spotlight on antibody–drug conjugates in cancer