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24-09-2018 | Breast cancer | Article

Progress in adjuvant systemic therapy for breast cancer

Journal: Nature Reviews Clinical Oncology

Authors: Noam F. Pondé, Dimitrios Zardavas, Martine Piccart

Publisher: Nature Publishing Group UK

Abstract

The prognosis of patients with early stage breast cancer has greatly improved in the past three decades. Following the first adjuvant endocrine therapy and chemotherapy trials, continuous improvements of clinical outcomes have been achieved through intense therapeutic escalation, albeit with increased health-care costs and treatment-related toxicities. In contrast to the advances achieved in surgery or radiotherapy, the identification of the patient subgroups that will derive clinical benefit from therapeutic escalation has proved to be a daunting process hindered by a lack of collaboration between scientific groups and by the pace of drug development. In the past few decades, initiatives towards de-escalation of systemic adjuvant treatment have achieved success. Herein, we summarize attempts to escalate and de-escalate adjuvant systemic treatment for patients with breast cancer and argue that new, creative trial designs focused on patients’ actual needs rather than on maximizing drug market size are needed. Ultimately, the adoption of effective treatments that do not needlessly expose patients and health-care systems to harm demands extensive international collaboration between academic groups, governments, and pharmaceutical companies.
Literature
1.
Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).
2.
NIH Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts — female breast cancer. SEER http://​seer.​cancer.​gov/​statfacts/​html/​breast.​html (2015).
3.
Bonadonna, G. et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 294, 405–410 (1976).PubMed
4.
[No authors listed.] Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by nolvadex adjuvant trial organisation. Lancet 1, 257–261 (1983).
5.
Denduluri, N. et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update. J. Clin. Oncol. 36, 23 (2018).
6.
Burstein, H. J. et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline update on ovarian suppression. J. Clin. Oncol. 34, 1689–1701 (2016).PubMed
7.
Sakorafas, G. H. & Safioleas, M. Breast cancer surgery: an historical narrative. Part, I. I. I. From the sunset of the 19th to the dawn of the 21st century. Eur. J. Cancer Care 19, 145–166 (2010).
8.
Zurrida, S. et al. The changing face of mastectomy (from mutilation to aid to breast reconstruction). Int. J. Surg. Oncol. 2011, 1–7 (2011).
9.
Veronesi, U. et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N. Engl. J. Med. 347, 1227–1232 (2002).PubMed
10.
Fisher, B. et al. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N. Engl. J. Med. 347, 567–575 (2002).PubMed
11.
Fisher, B. et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N. Engl. J. Med. 347, 1233–1241 (2002).PubMed
12.
Giuliano, A. E. et al. Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305, 569–575 (2011).PubMedPubMedCentral
13.
Giuliano, A. E. et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the american college of surgeons oncology group (alliance) acosog z0011 randomized trial. Ann. Surg. 264, 413–420 (2016).PubMed
14.
Donker, M. et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 15, 1303–1310 (2014).PubMedPubMedCentral
15.
Haviland, J. S. et al. The UK standardisation of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 14, 1086–1094 (2013).PubMed
16.
Vaidya, J. S. et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 383, 603–613 (2014).PubMed
17.
EBCTCG (Early Breast Cancer Trialists’ Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383, 2127–2135 (2014).
18.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378, 1707–1716 (2011).
19.
Livi, L. et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur. J. Cancer 51, 451–463 (2015).PubMed
20.
Polgár, C., Fodor, J., Major, T., Sulyok, Z. & Kásler, M. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 108, 197–202 (2013).
21.
Piccart, M. & Pondé, N. Cancer drugs, survival and ethics: a critical look from the inside. ESMO Open 1, e000149 (2017).PubMedPubMedCentral
22.
Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).PubMed
23.
Slamon, D. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273–1283 (2011).PubMedPubMedCentral
24.
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).PubMed
25.
Perez, E. A. et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J. Clin. Oncol. 32, 3744–3752 (2014).PubMedPubMedCentral
26.
Cameron, D. et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389, 1195–1205 (2017).PubMedPubMedCentral
27.
Lambertini, M., Pondé, N. F., Solinas, C. & de Azambuja, E. Adjuvant trastuzumab: a 10-year overview of its benefit. Expert Rev. Anticancer Ther. 17, 61–74 (2017).PubMed
28.
Piccart-Gebhart, M. et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J. Clin. Oncol. 34, 1034–1042 (2016).PubMed
29.
von Minckwitz, G. et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N. Engl. J. Med. 377, 122–131 (2017).
30.
Miller, K. D. Questioning our APHINITY for more. N. Engl. J. Med. 377, 186–187 (2017).PubMed
31.
Chan, A. et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 17, 367–377 (2016).PubMed
32.
Martin Jimenez, M. et al. 149O - Neratinib after trastuzumab (T)-based adjuvant therapy in early-stage HER2+ breast cancer (BC): 5-year analysis of the phase III ExteNET trial. Ann. Oncol. 28 (Suppl. 5), mdx362.001 (2017).
33.
Piccart, M. J. Why your preferred targeted drugs may become unaffordable. Cancer Res. 73, 5849–5851 (2013).PubMed
34.
Piccart-Gebhart, M. J. The 41st David A. Karnofsky memorial award lecture: academic research worldwide—quo vadis? J. Clin. Oncol. 32, 347–354 (2014).PubMed
35.
Simon, R. & Norton, L. The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens. Nat. Clin. Pract. Oncol. 3, 406–407 (2006).PubMed
36.
Bonilla, L. et al. Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. JNCI J. Natl Cancer Inst. 102, 1845–1854 (2010).PubMed
37.
Del Mastro, L. et al. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet 385, 1863–1872 (2015).PubMed
38.
Petrelli, F. et al. Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res. Treat. 151, 251–259 (2015).PubMed
39.
Foukakis, T. et al. Effect of tailored dose-dense chemotherapy versus standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial. JAMA 316, 1888 (2016).PubMed
40.
Gray, R. et al. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: an EBCTCG meta-analysis of 21,000 women in 16 randomised trials [abstract GS1-01]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-GS1-01 (2018).CrossRefPubMedPubMedCentral
41.
Curigliano, G. et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017. Ann. Oncol. 28, 1700–1712 (2017).
42.
Natori, A., Ethier, J.-L., Amir, E. & Cescon, D. W. Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials. Eur. J. Cancer 77, 40–47 (2017).PubMed
43.
Joensuu, H. et al. Adjuvant capecitabine in combination with docetaxel, epirubicin, and cyclophosphamide for early breast cancer: the randomized clinical FinXX trial. JAMA Oncol. 3, 793 (2017).PubMedPubMedCentral
44.
Masuda, N. et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N. Engl. J. Med. 376, 2147–2159 (2017).PubMed
45.
Jeruss, J. S. et al. Combined use of clinical and pathologic staging variables to define outcomes for breast cancer patients treated with neoadjuvant therapy. J. Clin. Oncol. 26, 246–252 (2008).PubMed
46.
Bonadonna, G. et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J. Clin. Oncol. 16, 93–100 (1998).PubMed
47.
Kwa, M., Makris, A. & Esteva, F. J. Clinical utility of gene-expression signatures in early stage breast cancer. Nat. Rev. Clin. Oncol. 14, 595–610 (2017).PubMed
48.
Bogaerts, J. et al. Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial. Nat. Clin. Pract. Oncol. 3, 540–551 (2006).PubMed
49.
Cardoso, F. et al. 70-Gene Signature as an aid to treatment decisions in early-stage breast cancer. N. Engl. J. Med. 375, 717–729 (2016).PubMed
50.
Tryfonidis, K. et al. Not all small node negative (pT1abN0) breast cancers are similar: outcome results from an EORTC 10041/BIG 3–04 (MINDACT) trial substudy [abstract 150O_PR]. Ann. Oncol. 28 (Suppl. 5), mdx440.003 (2017).
51.
Sparano, J. A. et al. Prospective validation of a 21-gene expression assay in breast cancer. N. Engl. J. Med. 373, 2005–2014 (2015).PubMedPubMedCentral
52.
Sparano, J. A. et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N. Engl. J. Med. 379, 111–121 (2018).PubMedPubMedCentral
53.
Harbeck, N. et al. Prospective WSG phase III PlanB trial: final analysis of adjuvant 4xEC→4x doc versus 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer. J. Clin. Oncol. 35 (15 Suppl.), Abstr. 504 (2017).
54.
Pan, H. et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N. Engl. J. Med. 377, 1836–1846 (2017).PubMedPubMedCentral
55.
Duffy, M. J. et al. Clinical use of biomarkers in breast cancer: updated guidelines from the european group on tumor markers (EGTM). Eur. J. Cancer 75, 284–298 (2017).PubMed
56.
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).PubMed
57.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).
58.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet 379, 432–444 (2012).
59.
Cardinale, D. et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J. Am. Coll. Cardiol. 55, 213–220 (2010).PubMed
60.
Jones, S. E. et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J. Clin. Oncol. 24, 5381–5387 (2006).PubMed
61.
Jones, S. et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US oncology research trial 9735. J. Clin. Oncol. 27, 1177–1183 (2009).PubMed
62.
Blum, J. L. et al. Anthracyclines in early breast cancer: the ABC trials—USOR 06–090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J. Clin. Oncol. 35, 2647–2655 (2017).PubMedPubMedCentral
63.
Janni, W. Pooled analysis of two randomized phase III trials (PlanB/SuccessC) comparing six cycles of docetaxel and cyclophosphamide to sequential anthracycline taxane chemotherapy in patients with intermediate and high risk HER2-negative early breast cancer (n = 5,923). J. Clin Oncol. 36 (15 Suppl.), Abstr. 522 (2018).
64.
Pondé, N. F., Lambertini, M. & de Azambuja, E. Twenty years of anti-HER2 therapy-associated cardiotoxicity. ESMO Open 1, e000073 (2016).PubMedPubMedCentral
65.
Giordano, S. H., Lin, Y.-L., Kuo, Y. F., Hortobagyi, G. N. & Goodwin, J. S. Decline in the use of anthracyclines for breast cancer. J. Clin. Oncol. 30, 2232–2239 (2012).PubMedPubMedCentral
66.
Slamon, D. et al. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer [abstract S5-04]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS15-S5-04 (2016).CrossRef
67.
Reeder-Hayes, K. E. et al. Comparative toxicity and effectiveness of trastuzumab-based chemotherapy regimens in older women with early-stage breast cancer. J. Clin. Oncol. 35, 3298–3305 (2017).PubMedPubMedCentral
68.
Tolaney, S. M. et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N. Engl. J. Med. 372, 134–141 (2015).PubMedPubMedCentral
69.
Tolaney, S. M. et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J. Clin. Oncol. 35, 511–511 (2017).
70.
Gianni, L. et al. 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. Lancet Oncol. 13, 25–32 (2012).PubMed
71.
Gianni, L. et al. 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 17, 791–800 (2016).PubMed
72.
Llombart-Cussac, A. et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 18, 545–554 (2017).PubMed
73.
Bianchini, G. et al. Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res. 19, 16 (2017).PubMedPubMedCentral
74.
Gianni, L. et al. 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. Lancet Oncol. https://​doi.​org/​10.​1016/​S1470-2045(18)30001-9 (2018).CrossRefPubMed
75.
Robertson, J. Peri-operative aromatase inhibitor treatment in determining or predicting long-term outcome in early breast cancer - the POETIC trial (CRUK/07/015) [abstract GS1-03]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-GS1-03 (2018).CrossRefPubMedPubMedCentral
76.
Gligorov, J. Early HER2-positive breast cancers: time for a new revolution? Lancet Oncol. https://​doi.​org/​10.​1016/​S1470-2045(17)30874-4 (2017).CrossRefPubMed
77.
Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).PubMedPubMedCentral
78.
Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 689–699 (2014).PubMed
79.
Hurvitz, S. A. et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. https://​doi.​org/​10.​1016/​S1470-2045(17)30716-7 (2017).CrossRefPubMedPubMedCentral
80.
Hofmann, D. et al. WSG ADAPT – adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial. Trials 14, 261 (2013).PubMedPubMedCentral
81.
Harbeck, N. et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)–positive early breast cancer (BC): final analysis of the west german study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor–positive phase II randomized trial—efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab Plus ET. J. Clin. Oncol. 35, 3046–3054 (2017).PubMed
82.
Mamounas, E. P. et al. A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): results from NRG oncology/NSABP B-42 [abstract S1-05]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS16-S1-05 (2017).CrossRef
83.
Tjan-Heijnen, V. C. G. et al. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. Lancet Oncol. 18, 1502–1511 (2017).PubMed
84.
Blok, E. J. et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006–2005). J. Natl Cancer Inst. 110, 40–48 (2018).
85.
Burstein, H. J. et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J. Clin. Oncol. 32, 2255–2269 (2014).PubMedPubMedCentral
86.
Goldvaser, H. et al. Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J. Clin. Oncol. 35, 549–549 (2017).
87.
Sestak, I. et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor–positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. https://​doi.​org/​10.​1001/​jamaoncol.​2017.​5524 (2018).CrossRefPubMedPubMedCentral
88.
Dowsett, M. et al. Integration of clinical variables for the prediction of late distant recurrence in patients with estrogen receptor-positive breast cancer treated with 5 years of endocrine therapy: CTS5. J. Clin. Oncol. 36, 1941–1948 (2018).PubMedPubMedCentral
89.
Pagani, O., Regan, M. M. & Fleming, G. F. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) versus tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials [abstract LBA1]. J. Clin. Oncol. https://​doi.​org/​10.​1200/​jco.​2014.​32.​18_​suppl.​lba1 (2018).CrossRef
90.
Pagani, O. et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N. Engl. J. Med. 371, 107–118 (2014).PubMedPubMedCentral
91.
Francis, P. A. et al. Adjuvant ovarian suppression in premenopausal breast cancer. N. Engl. J. Med. 372, 436–446 (2015).PubMed
92.
Francis, P. A. et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N. Engl. J. Med. https://​doi.​org/​10.​1056/​NEJMoa1803164 (2018).CrossRefPubMedPubMedCentral
93.
Bernhard, J. et al. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 16, 848–858 (2015).PubMedPubMedCentral
94.
Regan, M. M. et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials. J. Clin. Oncol. 34, 2221–2231 (2016).PubMedPubMedCentral
95.
Regan, M. M. Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) HER2-negative breast cancer (BC): results from TEXT and SOFT. J. Clin. Oncol. 36 (Suppl.), Abstract 503 (2018).
96.
Musgrove, E. A. & Sutherland, R. L. Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631–643 (2009).PubMed
97.
Turner, N. C. et al. Palbociclib in hormone-receptor–positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).PubMed
98.
Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).PubMed
99.
Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35, 3638–3646 (2017).PubMed
100.
LoRusso, P. M. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J. Clin. Oncol. https://​doi.​org/​10.​1200/​JCO.​2014.​59.​0018 (2016).CrossRefPubMedPubMedCentral
101.
Baselga, J. et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).PubMed
102.
Royce, M. et al. BOLERO-4: phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (BC). Ann. Oncol. https://​doi.​org/​10.​1093/​annonc/​mdw365.​01 (2016).CrossRef
103.
André, F. et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 15, 267–274 (2014).PubMed
104.
Hurvitz, S. A. et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 16, 816–829 (2015).PubMed
105.
Rugo, H. S. et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 18, 654–662 (2017).PubMed
106.
Baselga, J. et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 904–916 (2017).PubMedPubMedCentral
107.
Di Leo, A. et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 19, 87–100 (2018).PubMed
108.
Loibl, S. et al. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: a randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur. J. Cancer 85, 133–145 (2017).PubMedPubMedCentral
109.
Saura, C. et al. Primary results of LORELEI: a phase II randomised double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative early stage breast cancer. Ann. Oncol. (Suppl. 5), mdx440.001 (2017).
110.
Glassman, D., Hignett, S., Rehman, S., Linforth, R. & Salhab, M. Adjuvant endocrine therapy for hormone-positive breast cancer, focusing on ovarian suppression and extended treatment: an update. Anticancer Res. 37, 5329–5341 (2017).PubMed
111.
Colleoni, M. et al. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. https://​doi.​org/​10.​1016/​S1470-2045(17)30715-5 (2017).CrossRefPubMed
112.
Song, R. X.-D. et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17 -estradiol. J. Natl Cancer Inst. 93, 1714–1723 (2001).PubMed
113.
Lewis, J. S., Osipo, C., Meeke, K. & Jordan, V. C. Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal. J. Steroid Biochem. Mol. Biol. 94, 131–141 (2005).PubMed
114.
Lambertini, M., Goldrat, O., Clatot, F., Demeestere, I. & Awada, A. Controversies about fertility and pregnancy issues in young breast cancer patients: current state of the art. Curr. Opin. Oncol. 29, 243–252 (2017).PubMed
115.
Azim, H. A. et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J. Clin. Oncol. 31, 73–79 (2013).PubMed
116.
Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724–734 (2015).PubMedPubMedCentral
117.
Blackwell, K. L. et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 28, 1124–1130 (2010).PubMed
118.
Baselga, J. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379, 633–640 (2012).PubMedPubMedCentral
119.
de Azambuja, E. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 15, 1137–1146 (2014).PubMed
120.
Baselga, J. Patient (pt)-reported function and symptoms in APHINITY: a randomized comparison of chemotherapy (C) + trastuzumab (H) + placebo (Pla) versus C + H + pertuzumab (P) as adjuvant therapy in pts with HER2-positive early breast cancer (EBC). J. Clin. Oncol. 36 (15 Suppl.), Abstr. 521 (2018).
121.
Goldhirsch, A. et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382, 1021–1028 (2013).PubMed
122.
Delaloge, S. et al. Effects of neratinib on health-related quality of life (HRQoL) in early-stage HER2+ breast cancer: longitudinal analyses from the phase III ExteNET trial [abstract 177P]. Ann. Oncol. https://​doi.​org/​10.​1093/​annonc/​mdx362.​027 (2017).CrossRefPubMedPubMedCentral
123.
Joensuu, H. et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 354, 809–820 (2006).PubMed
124.
Pivot, X. et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 14, 741–748 (2013).PubMed
125.
Earl, H. M. et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J. Clin Oncol. 36 (15 Suppl.), Abstr. 506 (2018).
126.
Mavroudis, D. et al. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann. Oncol. 26, 1333–1340 (2015).PubMed
127.
Conte, P. F. et al. 9 weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian study Short-HER. J. Clin. Oncol. 35, 501–501 (2017).
128.
Joensuu, H. et al. A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer (the SOLD study) [abstract GS3-04]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-GS3-04 (2018).CrossRef
129.
Earl, H. M. et al. Trastuzumab-associated cardiac events in the persephone trial. Br. J. Cancer 115, 1462–1470 (2016).PubMedPubMedCentral
130.
Katz, H. & Alsharedi, M. Immunotherapy in triple-negative breast cancer. Med. Oncol. Northwood Lond. Engl. 35, 13 (2017).
131.
Loi, S. et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study [abstract GS2-06]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-GS2-06 (2018).CrossRef
132.
Teng, M. W. L., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).PubMedPubMedCentral
133.
Mahoney, K. M. et al. PD-L1 antibodies to its cytoplasmic domain most clearly delineate cell membranes in immunohistochemical staining of tumor cells. Cancer Immunol. Res. 3, 1308–1315 (2015).PubMedPubMedCentral
134.
Goodman, A. M. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16, 2598–2608 (2017).PubMedPubMedCentral
135.
Domchek, S. et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC) [abstract PD6-11]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-PD6-11 (2018).CrossRefPubMedPubMedCentral
136.
Loi, S. et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 25, 1544–1550 (2014).PubMed
137.
Loibl, S. et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (HER2) therapy in primary HER2-overexpressing breast cancer. J. Clin. Oncol. 32, 3212–3220 (2014).PubMed
138.
Loi, S. et al. Effects of estrogen receptor and human epidermal growth factor receptor-2 levels on the efficacy of trastuzumab: a secondary analysis of the HERA trial. JAMA Oncol. https://​doi.​org/​10.​1001/​jamaoncol.​2016.​0339 (2016).CrossRefPubMed
139.
Salgado, R. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 1, 448–454 (2015).PubMedPubMedCentral
140.
Sonnenblick, A. et al. Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer. BMC Med. https://​doi.​org/​10.​1186/​s12916-015-0416-2 (2015).CrossRefPubMedPubMedCentral
141.
Berns, K. et al. Loss of ARID1A activates ANXA1, which serves as a predictive biomarker for trastuzumab resistance. Clin. Cancer Res. https://​doi.​org/​10.​1158/​1078-0432 (2016).CrossRefPubMedPubMedCentral
142.
Hall, J. A., Salgado, R., Lively, T., Sweep, F. & Schuh, A. A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group. Lancet Oncol. 15, e184–e193 (2014).PubMed
143.
Taube, S. E. et al. A Perspective on challenges and issues in biomarker development and drug and biomarker codevelopment. JNCI 101, 1453–1463 (2009).PubMedPubMedCentral
144.
Suman, V. J., Ellis, M. J. & Ma, C. X. The ALTERNATE trial: assessing a biomarker driven strategy for the treatment of post-menopausal women with ER+/Her2- invasive breast cancer. Chin. Clin. Oncol. https://​doi.​org/​10.​3978/​j.​issn.​2304-3865.​2015.​09.​01 (2015).CrossRefPubMedPubMedCentral
145.
Nitz, U. A. et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann. Oncol. 28, 2768–2772 (2017).PubMed
146.
Gluz, O. et al. Comparison of neoadjuvant nab-paclitaxel+carboplatin versus nab-paclitaxel+gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. JNCI https://​doi.​org/​10.​1093/​jnci/​djx258 (2017).CrossRef
147.
Dowsett, M. et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin. Cancer Res. 11, 951s–958s (2005).PubMed
148.
Harrington, D. & Parmigiani, G. I-SPY 2 — a glimpse of the future of phase 2 drug development? N. Engl. J. Med. 375, 7–9 (2016).PubMed
149.
Park, J. W. et al. Adaptive randomization of neratinib in early breast cancer. N. Engl. J. Med. 375, 11–22 (2016).PubMedPubMedCentral
150.
Rugo, H. S. et al. Adaptive randomization of veliparib–carboplatin treatment in breast cancer. N. Engl. J. Med. 375, 23–34 (2016).PubMedPubMedCentral
151.
Wan, J. C. M. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).PubMed
152.
Dawson, S.-J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).PubMed
153.
Murtaza, M. et al. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat. Commun. 6, 8760 (2015).PubMed
154.
Zill, O. et al. Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J. Clin. Oncol. 34 (18 Suppl.), LBA11501 (2016).
155.
Fribbens, C. et al. Plasma ESR1 mutations and the treatment of estrogen receptor–positive advanced breast cancer. J. Clin. Oncol. 34, 2961–2968 (2016).PubMed
156.
Ignatiadis, M. et al. Circulating tumor DNA in HER2 amplified breast cancer: a translational research substudy of the NeoALTTO phase 3 trial [abstract PD3-03]. Cancer Res. https://​doi.​org/​10.​1158/​1538-7445.​SABCS17-PD3-03 (2018).CrossRef
157.
Olsson, E. et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol. Med. 7, 1034–1047 (2015).PubMedPubMedCentral
158.
Garcia-Murillas, I. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci. Transl Med. 7, 302ra133 (2015).PubMed
159.
Veronesi, U. et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N. Engl. J. Med. 349, 546–553 (2003).PubMed
160.
Mansel, R. E. et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. JNCI 98, 599–609 (2006).PubMed
161.
Krag, D. N. et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 11, 927–933 (2010).PubMedPubMedCentral
162.
Whelan, T. J. et al. Long-term results of hypofractionated radiation therapy for breast cancer. N. Engl. J. Med. 362, 513–520 (2010).PubMed
163.
Strnad, V. et al. 5-Year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 387, 229–238 (2016).PubMed
164.
Veronesi, U. et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 14, 1269–1277 (2013).PubMed
165.
Hughes, K. S. et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J. Clin. Oncol. 31, 2382–2387 (2013).PubMedPubMedCentral
166.
Fyles, A. W. et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N. Engl. J. Med. 351, 963–970 (2004).PubMed
167.
Müller, B. M. et al. The EndoPredict gene-expression assay in clinical practice - performance and impact on clinical decisions. PLOS ONE 8, e68252 (2013).PubMedPubMedCentral