Management of Stage IV Metastatic Breast Cancer in a Premenopausal Women

  • The recommended initial treatment regimen:
    • For premenopausal women with:
      • De novo stage IV ER-positive breast cancer is:
        • Endocrine therapy + ovarian ablation/suppression
  • With ovarian ablation / suppression:
    • The choice of endocrine therapy becomes similar to that of postmenopausal women and may include:
      • Tamoxifen or an aromatase inhibitor
  • New research focusing on the:
    • Cyclin-dependent kinase 4/6 inhibitors (CDK):
      • Is emerging in this setting as well:
        • And could be added to endocrine therapy with ovarian function suppression
  • Investigation began:
    • In the postmenopausal patient population
  • The PALOMA-1 trial:
    • Randomized postmenopausal women with advanced-stage, ER-positive, HER2-negative breast cancer to either:
      • Letrozole alone or letrozole in combination with palbociclib (CDKs 4 and 6 inhibitor):
        • Who had not received any systemic therapy
    • Median progression-free survival was:
      • 10.2 months versus 20.2 months:
        • In the letrozole group versus the palbociclib plus letrozole groups respectively:
          • p=0.0004
    • This phase 2 study:
      • Led to the FDA approval of palbociclib:
        • For treatment of postmenopausal women with ER-positive, HER2-negative:
          • Metastatic breast cancer
  • Phase 3 studies are ongoing:
    • However, the PALOMA-3 trial:
      • Randomized 521 women with ER-positive, HER2-negative metastatic breast cancer:
        • Who had progressed on prior endocrine therapy to:
          • Palbociclib plus fulvestrant or fulvestrant plus placebo
      • Median progression-free survival:
        • Was 9.5 months in those receiving fulvestrant plus palbociclib versus 4.6 months in those receiving fulvestrant plus placebo
          • p<0.0001
      • These data suggest an emerging role for CDK inhibitors:
        • In women with ER-positive, HER2-negative advanced disease
  • In the metastatic setting:
    • Neither radiation nor surgical resection of the primary tumor at diagnosis:
      • Have conclusively been shown to:
        • Improve overall survival
    • This question has been evaluated in several retrospective and large database series concluding optimistic results:
      • However:
        • These data are limited by significant selection bias
  • Two randomized controlled trials also address this question:
    • Badwe et al randomly assigned 350 patients with de novo stage IV breast cancer:
      • To receive locoregional therapy to the primary breast tumor and axilla or to no locoregional treatment
        • They stratified patients by:
          • Site of distant metastasis
          • Number of distant metastases
          • Hormone receptor status
      • Median overall survival was:
        • 19.2 months:
          • In those randomized to locoregional treatment and
        • 20.5 months:
          • In those in the no-locoregional treatment group
            • p=0.79
      • The investigators concluded:
        • There was no evidence that local treatment of the primary tumor:
          • Affects overall survival in patients with de novo stage IV disease who have responded chemotherapy
  • Second, Soran et al randomly assigned 274 women with treatment-naive stage IV breast cancer:
    • To local regional surgery plus systemic therapy versus systemic therapy alone
    • At a median follow-up of 40 months:
      • Overall survival was:
        • 46 months in the surgery group compared to only 36 months in the systemic therapy group
    • Unplanned subgroup analyses were performed:
      • And concluded overall survival was statistically higher in:
        • The surgery group than in the systemic therapy group in hormone receptor-positive, HER2-negative patients
          • HR: 0.64, p=0.01
        • In patients less than 55 years
          • HR 0.57, p = 0.006
        • In those with solitary bone-only metastasis
          • HR: 0.47, p = 0.04
    • The authors concluded:
      • There may be a benefit to locoregional surgery
  • In the US, E2108 is an ongoing randomized trial addressing this question as well
  • References:
    • Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial. Lancet Oncol. 2015;16(13):1380-1388.
    • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines for Oncology: Breast Cancer. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp Published January 2016. Accessed January 31, 2017.
    • Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(29):3307-3329.
    • Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
    • Cristofanilli M, Turner NC, Bondarenko I, 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(4):425-439.
    • Atilla Soran, Vahit Ozmen, Serdar Ozbas, et al. A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01). J Clin Oncol. 2016;34(suppl; abstr 1005).

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #Cancer #BreastCancer #Teacher

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