A prospective, phase II, neoadjuvant study based on chemotherapy sensitivity in HR+/HER2- breast cancer-FINEST study

Abstract

Background: Hormone receptor-positive (HR+)/humaal growth factor receptor 2-negative (HER2-) breast cancer, the most common breast cancer type, has variable prognosis and high recurrence risk. Neoadjuvant therapy is recommended for median-high risk HR+/HER2- patients. This phase II, single-arm, prospective study aimed to explore appropriate neoadjuvant treatment strategies for HR+/HER2- breast cancer patients.

Methods: Eligible female patients with newly diagnosed, untreated HR+/HER2- breast cancer received 2 cycles of nab-paclitaxel and carboplatin (nabPCb). Magnetic resonance imaging (MRI) was performed to assess tumor responses, and ≥40% regression of the maximal tumor diameter was deemed chemo-sensitive. Chemo-sensitive patients continued nabPCb for 4 more cycles (group A). Chemo-insensitive patients were randomized to groups B, C, and D at a ratio of 1:3:1 to receive a new chemotherapy for 4 cycles or endocrine-immune-based therapy (dalpiciclib, letrozole and adebrelimab, with goserelin if patients were premenopausal) for 4 cycles or to undergo surgery. Peripheral blood and core-needle biopsy (CNB) samples were collected before treatment, followed by a next-generation sequencing (NGS) panel detection and similarity network fusion (SNF) typing through digital pathology data. The primary endpoint was the pathological complete response (pCR) rate, and the secondary endpoint was the clinical objective response rate (ORR).

Results: A total of 121 patients were enrolled (67.8% with stage III disease), with 76, 9, 27, and 9 patients in groups A, B, C and D, respectively. The total pCR rate was 4.1%, and all patients who received pCR were in group A. Group C had a better ORR than Group B (81.5% vs. 66.7%). Exploratory analysis revealed that patients with the SNF4 subtype were the most sensitive to nabPCb (pCR rate of 21.1% vs. 1.8% in group A), whereas patients in group C with the SNF2 subtype were more sensitive to endocrine-immune-based therapy (Miller-Payne grade 4-5, 45.5% vs. 6.3%).

Conclusions: Converting to endocrine-immune-based therapy improved the ORR, but not the pCR rate in chemo-insensitive patients. Neoadjuvant chemotherapy and endocrine therapy are not mutually exclusive. The SNF4 subtype of HR+/HER2- breast cancer was more chemo-sensitive, whereas the SNF2 subtype might be more sensitive to immunotherapy.

Keywords

breast cancer / HR / HER2 / neoadjuvant therapy / SNF subtype / precision treatment

References

[1] Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020; 37(4): 496–513.

[2] Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001; (30): 96–102.

[3] Kaufmann M, von Minckwitz G, Smith R, Valero V, Gianni L, Eiermann W, et al. International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations. J Clin Oncol. 2003; 21(13): 2600–2608.

[4] von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012; 30(15): 1796–1804.

[5] Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia J, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008; 26(8): 1275–1281.

[6] Cortazar P, Zhang L, Untch M, Mehta K, Jonkers J, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014; 384(9938): 164–172.

[7] Schmid P, Rugo HS, Adams S, Schneeweiß A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020; 21(1): 44–59.

[8] Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020; 396(10257): 1090–1100.

[9] Loi S, Curigliano G, Salgado R, et al. Biomarker results in high-risk estrogen receptor positive, human epidermal growth factor receptor 2 negative primary breast cancer following neoadjuvant chemotherapy ± nivolumab: an exploratory analysis of CheckMate 7FL. 2023 SABCS abstract GS01-01.

[10] Cardoso F, Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal. Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high risk ER+/HER2- breast cancer: KEYNOTE-756. 2023 SABCS abstract GS01-02.

[11] von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013; 31(29): 3623–3630.

[12] Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, et al. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2016; 2(11): 1477–1486.

[13] Cottu P, D'Hondt V, Dureau S, Lerebours F, Lerebours F, Desmoulins I, Ray-Coquard I, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol, 2018; 29(12): 2334–2340.

[14] Guerrero-Zotano AL, Arteaga CL. Neoadjuvant Trials in ER(+) Breast Cancer: A Tool for Acceleration of Drug Development and Discovery. Cancer Discov. 2017; 7(6): 561–574.

[15] Nitz U, Gluz O, Kreipe HH, Christgen M, Küemmel S, Baehner FL, et al. The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer. Ther Adv Med Oncol. 2020; 12: 1758835920973130.

[16] Ma CX, Suman VJ, Sanati S, Vij K, Anurag M, Leitch AM, et al. Endocrine-sensitive disease rate in postmenopausal patients with estrogen receptor-rich/ERBB2-negative breast cancer receiving neoadjuvant anastrozole, fulvestrant, or their combination: a phase 3 randomized clinical trial. JAMA Oncol. 2024; 10(3): 362–371.

[17] Ellis MJ, Suman VJ, Hoog J, Gonçalves R, Sanati S, Creighton CJ, et al. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017; 35(10): 1061–1069.

[18] Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018; 378(2): 158–168.

[19] Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chávez A, Keegan N, Khamashta MA, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020; 6(1): 38.

[20] Jin X, Zhou YF, Ma D, Zhao S, Lin CJ, Xiao Y, et al. Molecular classification of hormone receptor-positive HER2-negative breast cancer. Nat Genet. 2023; 55(10): 1696–1708.

[21] Lang GT, Jiang YZ, Shi JX, Yang F, Li X, Pei Y-C, et al. Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing. Nat Commun. 2020; 11(1): 5679.

[22] Kaufmann M, Hortobagyi GN, Goldhirsch A, Scholl S, Makris A, Valagussa P, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol. 2006; 24(12): 1940–1949.

[23] Bear HD, Anderson S, Smith RE, Geyer Jr CE, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006; 24(13): 2019–2027.

[24] Pérez-García JM, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Powles T, et al. Chemotherapy de-escalation using an (18)F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021; 22(6): 858–871.

[25] Hylton NM, Blume JD, Bernreuter WK, Pisano ED, Rosen M, Morris EA, et al. Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy–results from ACRIN 6657/I-SPY TRIAL. Radiology. 2012; 263(3): 663–672.

[26] Reig B, Lewin AA, Du L, Heacock L, Toth HK, Heller SL, et al. Breast MRI for evaluation of response to neoadjuvant therapy. Radiographics. 2021; 41(3): 665–679.

[27] Hurvitz SA, Martin M, Press MF, Chan D, Fernandez-Abad M, Petru E, et al. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR(+)/HER2(-) Breast Cancer. Clin Cancer Res. 2020; 26(3): 566–580.

[28] Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates KE, et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2018; 8(2): 216–233.

[29] Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A'Hern R, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007; 99(2): 167–170.

[30] Chen XS, Nie XQ, Chen CM, Wu J, Lu J, Shao Z-M, et al. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2010; 21(5): 961–967.

[31] Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 26(5): 778–785.

[32] Litton JK, Regan MM, Pusztai L, Rugo HS, Tolaney SM, Tolaney SM, Garrett-Mayer E, et al. Standardized definitions for efficacy end points in neoadjuvant breast cancer clinical trials: NeoSTEEP. J Clin Oncol. 2023; 41(27): 4433–4442.

[33] Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012; 366(26): 2438–2441.

[34] Basile D, Cinausero M, lacono D, Pelizzari G, Bonotto M, Giacomo AMD, et al. Androgen receptor in estrogen receptor positive breast cancer: Beyond expression. Cancer Treat Rev. 2017; 61: 15–22.

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2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.