Cancer Res Treat.  2021 Jul;53(3):695-702. 10.4143/crt.2020.1246.

Implications of Tamoxifen Resistance in Palbociclib Efficacy for Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Subgroup Analyses of KCSG-BR15-10 (YoungPEARL)

Affiliations
  • 1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 2Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  • 3Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
  • 4Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 5Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
  • 6Center for Breast Cancer, National Cancer Center, Goyang, Korea
  • 7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  • 8Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea

Abstract

Purpose
YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and Methods Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC.
Results
In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2– MBC patients irrespective of tamoxifen sensitivity.

Keyword

Breast neoplasms; Tamoxifen; CDK4/6 inhibitor; Palbociclib; Endocrine therapy

Figure

  • Fig. 1 Forest plot of subgroup analysis for progression-free survival. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; PS, performance status.

  • Fig. 2 Progression-free survival curves according to tamoxifen sensitivity for ITT population (20.2 months vs. 15.1 months) (A), palbociclib plus endocrine therapy arm (20.5 months vs. 20.1 months) (B), and capecitabine arm (12.6 months vs. 14.5 months) (C). (D) Progression-free survival curves according to tamoxifen sensitivity and treatment arms. CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; ITT, intention-to-treat; NA, not available.


Reference

References

1. Preusser M, De Mattos-Arruda L, Thill M, Criscitiello C, Bartsch R, Ruhstaller T, et al. CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. ESMO Open. 2018; 3:e000368.
Article
2. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer. 2019; 5:27.
Article
3. Shah AN, Metzger O, Bartlett CH, Liu Y, Huang X, Cristofanilli M. Hormone receptor-positive/human epidermal growth receptor 2-negative metastatic breast cancer in young women: emerging data in the era of molecularly targeted agents. Oncologist. 2020; 25:e900–8.
Article
4. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016; 375:1925–36.
Article
5. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. 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. 2016; 17:425–39.
Article
6. Park YH, Kim TY, Kim GM, Kang SY, Park IH, Kim JH, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019; 20:1750–9.
7. Kim JY, Kang D, Nam SJ, Kim SW, Lee JE, Yu JH, et al. Clinical features and outcomes of invasive breast cancer: age-specific analysis of a modern hospital-based registry. J Glob Oncol. 2019; 5:1–9.
Article
8. Yeo W, Ueno T, Lin CH, Liu Q, Lee KH, Leung R, et al. Treating HR+/HER2− breast cancer in premenopausal Asian women: Asian Breast Cancer Cooperative Group 2019 Consensus and position on ovarian suppression. Breast Cancer Res Treat. 2019; 177:549–59.
Article
9. Finn RS, Gelmon KA, Ettl J, Asselah J, Castrellon A, Ruiz Simón A, et al. Impact of prior treatment on palbociclib plus letrozole (P+L) efficacy and safety in patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2–) first-line advanced breast cancer (ABC): a PALOMA-2 subgroup analysis. Ann Oncol. 2017; 28(Suppl 5):v79–80.
Article
10. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018; 29:1634–57.
Article
11. Taylor CW, Green S, Dalton WS, Martino S, Rector D, Ingle JN, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998; 16:994–9.
Article
12. Anders CK, Hsu DS, Broadwater G, Acharya CR, Foekens JA, Zhang Y, et al. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol. 2008; 26:3324–30.
Article
13. Liao S, Hartmaier RJ, McGuire KP, Puhalla SL, Luthra S, Chandran UR, et al. The molecular landscape of premenopausal breast cancer. Breast Cancer Res. 2015; 17:104.
Article
14. Kan Z, Ding Y, Kim J, Jung HH, Chung W, Lal S, et al. Multi-omics profiling of younger Asian breast cancers reveals distinctive molecular signatures. Nat Commun. 2018; 9:1725.
Article
15. Yap YS, Lu YS, Tamura K, Lee JE, Ko EY, Park YH, et al. Insights into breast cancer in the East vs the West: a review. JAMA Oncol. 2019; 5:1489–96.
16. Lin CH, Yap YS, Lee KH, Im SA, Naito Y, Yeo W, et al. Contrasting epidemiology and clinicopathology of female breast cancer in Asians vs the US population. J Natl Cancer Inst. 2019; 111:1298–306.
Article
17. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009; 36:237–49.
Article
18. Park YH, Lee SJ, Jung HA, Kim SM, Kim MJ, Kil WH, et al. Prevalence and clinical outcomes of young breast cancer (YBC) patients according to intrinsic breast cancer subtypes: Single institutional experience in Korea. Breast. 2015; 24:213–7.
Article
19. Ahn SH, Son BH, Kim SW, Kim SI, Jeong J, Ko SS, et al. Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea: a report from the Korean Breast Cancer Society. J Clin Oncol. 2007; 25:2360–8.
20. Kim TY, Ahn JH, Yoon JH, Sohn JH, Kim GM, Lee KH, et al. Abstract P1-09-09: role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07). Cancer Res. 2016; 76(4 Suppl):P1-09-09.
Article
21. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018; 19:904–15.
Article
22. Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019; 381:307–16.
Article
23. Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018; 379:1926–36.
Article
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