Neoadjuvant Endocrine Therapy

  • Women with early-stage breast cancer:
    • Typically undergo surgery up front
  • While women with more advanced disease:
    • Larger tumors
    • Locally advanced tumors
    • High grade tumors
    • Lymph node positive
    • Triple-negative breast cancer
    • HER2-positive breast cancer:
      • May benefit from neoadjuvant therapy
  • The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial:
    • Randomized 330 postmenopausal women with:
      • ER-positive breast cancer
      • Invasive breast cancer
      • Non-metastatic breast cancer
      • Operable breast cancer
      • Locally advanced potentially operable breast cancer:
        • To neoadjuvant:
          • Tamoxifen, anastrozole, or a combination of tamoxifen and anastrozole:
            • For three months
    • Among patients enrolled:
      • The median age was 73
      • The median tumor size was 4 cm
      • No chemotherapy was given
    • Overall response rates:
      • Were similar among the three arms:
        • At a median of 13 weeks
    • In patients who were assessed as requiring mastectomy at baseline (n = 124):
      • 44% received breast-conserving surgery after anastrozole and
      • 31% after tamoxifen
        • p = .23
  • Importantly:
    • pCR is rare:
      • With neoadjuvant endocrine therapy
  • There have not been any Phase III randomized trials:
    • Comparing neoadjuvant chemotherapy to neoadjuvant endocrine therapy
  • A number of clinical trials have reported:
    • Conversion rates of mastectomy to breast-conserving surgery:
      • Ranging from 30% to 88%
  • In the ACOSOG Z1031 trial:
    • Ki67 reduction:
      • Was associated with response to:
        • Neoadjuvant aromatase inhibitor therapy
    • Tumor Ki67 levels determined after initiation:
      • Of neoadjuvant endocrine treatment:
        • Are more prognostic than baseline analysis
  • Ellis et al described a:
    • Preoperative endocrine prognostic index (PEPI) score:
      • In which Ki67 data have been integrated into a post-treatment model that also includes:
        • Pathologic stage and ER levels
          • Patients with pathologically node-negative, T1 or T2 disease with a:
            • Fully suppressed Ki67 level (2.7% or 1% on a natural log scale) and persistent ER expression:
              • After completion of neoadjuvant endocrine therapy (PEPI of 0):
                • Were found to have such a low risk of relapse that:
                  • Adjuvant chemotherapy after neoadjuvant endocrine therapy:
                    • May not be necessary
  • In the letrozole vs tamoxifen P024 trial:
    • The relationship between ER expression by Allred score and log odds of response fit a linear model that was significant by logistic regression
  • A recent systematic review and meta-analysis of 20 prospective, randomized, neoadjuvant clinical trials:
    • That reported response rates concluded:
      • Neoadjuvant endocrine therapy with aromatase inhibitors resulted in a similar clinical and radiological response rate and breast conservation surgery rate but:
        • With lower toxicity than combination chemotherapy
    • Patients treated with aromatase inhibitors:
      • Had a higher clinical tumor response rates than those treated with tamoxifen
    • Overall, the pathologic complete response was:
      • Less than 10% in the review
  • References:
    • Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23(22):5108-5116.
    • Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11(2):155-168.
    • Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor–rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype – ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342-2349.
    • Olson JA Jr, Budd GT, Carey LA, et al. Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: Results from a multicenter phase II trial. J Am Coll Surg. 2009;208(5):906-914.
    • Dowsett M, Smith IE, Ebbs SR, 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. 2005;11(2 Pt 2):951s-958s.
    • Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized doubleblind multicenter study. Ann Oncol. 2001;12(11):1527-1532.

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