Neoadjuvant Chemotherapy (NAC)

Neoadjuvant Chemotherapy (NAC)

• Neoadjuvant chemotherapy (NAC):
  • Refers to the delivery of systemic treatment prior to surgery
• Preoperative chemotherapy was initially utilized in women with locally advanced or inflammatory breast cancers:
  • To improve operability
• Among women with early-stage breast cancers:
  • The NSABP B-18 and B-27 randomized clinical trials:
    • Demonstrated no difference in:
      • Disease-specific or overall survival:
        • Between those who received neoadjuvant versus adjuvant chemotherapy
    • Neoadjuvant chemotherapy:
      • Improved rates of breast conservation:
        • 68% versus 60%
• More recent observational data have demonstrated:
  • No increased risk in surgical complications among women who underwent neoadjuvant chemotherapy
• NAC has more recently been used to:
  • Downstage the axilla in patients with biopsy-proven lymph node involvement with hopes to avoid completion lymphadenectomy and decrease the risk of lymphedema
• Additionally, NAC has been used in women with operable breast cancers:
  • To theoretically treat micro-metastatic disease prior to local therapy and to allow assessment of the in vivo tumor response to certain chemotherapy regimens
• Notably, results from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis included:
  • Patient-level data from 4,756 women enrolled in clinical trials 1983 to 2002:
    • Results demonstrated a higher risk of in-breast recurrence after neoadjuvant chemotherapy:
      • At 15 years, women treated with NAC had a 21% risk of local recurrence (vs. 16% in the surgery-first patients):
        • This was attributed to a higher rate of breast conservation, but with no difference in distant recurrence or breast cancer-specific overall survival
• Among women with operable breast cancers at the time of diagnosis:
  • Neoadjuvant chemotherapy (NAC) is increasingly used to gain information about the tumor’s response to treatment:
    • With pathologic response rates correlating with long-term prognosis
• ·         The most accepted definition of pathologic complete response (pCR):

• Although this definition varies:
  • Residual in situ disease does not affect the risk of distant recurrence
• Response to preoperative treatment differs by tumor biology:
  • With hormone-receptor positive breast cancer patients:
    • Having the lowest overall pCR rate
• For some women with residual disease, including those with HER2-positive and triple-negative breast cancers:
  • This allows for use of additional adjuvant therapy that improves cancer outcomes including:
    • Receipt of TDM-1 (trastuzumab emtansine, KATHERINE Trial)
    • Xeloda (CREATE-X Trial), or
    • Eligibility for ongoing clinical trials
• Notably, recent changes to the American Joint Committee on Cancer Staging System includes:
  • Pathologic stage after neoadjuvant chemotherapy as part of the updated system:
    • When pCR is achieved in both the breast and axillary nodes:
      • Survival is driven by response to chemotherapy compared to initial presenting stage
• ·         Choosing a NAC regimen depends on tumor biology:

• Chemotherapy should be combined with HER2-targeted therapies:
  • i.e., Taxane + carboplatin + trastuzumab, pertuzumab (TCHP)
  • HER2-negative patients:
    • Anthracycline-based drugs including:
      • Doxorubicin and cyclophosphamide followed by a taxane
  • Higher risk HER2-negative breast cancers (node-positive hormone-receptor positive patients and triple-negative patients) typically receive:
    • Anthracycline and taxane-based regimens with or without carboplatin
  • Notably, results from the CALGB 406034 trial:
    • Suggested that for triple-negative breast cancer:
      • The addition of carboplatin to NAC resulted in a 14% increase in eligibility for breast conservation

• References
  • Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16(8): 2672-2685.
  • Boughey J, Peintinger F, Meric-Bernstam F, Perry AC, Hunt KK, Babiera GV, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg. 2006;244(3):464-470.
  • Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomized trials. Lancet Oncol. 2018;19(1):27-39.
  • Fayanju OM, et al. The Clinical Significance of Breast-only and Node-only Pathologic Complete Response After Neoadjuvant Chemotherapy. Annals of Surgery. 2018; 268(4): 591-601.
  • von Minckwitz, G et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. NEJM. 2018; 380(7): 617-628.
  • Masuda N, et al. Adjuvant Capecitabine for Breast Cancer After Preoperative Chemotherapy. NEJM. 2017; 376:2147-59.
  • Golshan M, et al. Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: surgical results from CALGB 40603 (Alliance). Annals of Surgery. 2015; Sep; 262(3):434-9.

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