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).

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