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Neoadjuvant Therapy in Breast Cancer

Indications

As per the 2024 NCCN guidlines

  • Early breast cancer
    • HER2+ and Triple negative
      • 2024 NCCN guidlines states “preferred” in T2+ or N1+ and “can be considered” in T1 N0
    • Large primary tumour relative to breast size in a patient who desires breast conservation
    • cN+ disease likely to become cN0 with preoperative systemic therapy
      • Avoid ALND if SNB clear
  • Locally Advanced breast cancer
    • Patients with inoperable breast cancer
      • Bulky or matted cN2 axillary nodes
      • cN3 nodes
        • Note the clinical staging of LN is different to pathological staging
          • N1 - movable metastasis to any number of level I or II nodes
          • N2 - fixed or mattered level I or II nodes
          • N3 - Infraclavicular, supraclavicular or axilar + internal mammary
      • cT4 tumors (note T3 included in early)
      • Inflammatory breast cancer
  • Temporary Contraindications to Surgery
    • Breast cancer during pregnancy
    • In patients that surgery needs to be delayed
      • E.g Need for short term anticoagulation (DVT, PE, Drug eluting stent etc)

Benefits

  • Downstage
    • Facilitates breast conservation
      • Reduces size often by 50-80%
    • Can render inoperable tumors operable
  • Prognostic information
    • Allows for complete pathological response
    • In patients with residual disease second line chemotherapy can be used
      • Patients are at higher risk for relapse
      • Allow for the addition of supplemental adjuvant regimens, particularly in patients with TNBC or HER2-positive breast cancer.
  • Time
    • Allows time for genetic testing
    • Allows time to plan breast reconstruction in patients electing mastectomy
    • Allows time for delayed decision-making for definitive surgery

General notes

  • Pathological complete response is associated with increased survival
    • More likely seen in young, ER/PR –ve, HER2+ve patients
      • Although overall outlook of HER-2 +ve tumours worse
    • Herceptin + chemo improves rates of complete response
  • Need to assess and document extent of disease before starting
    • Required for staging, but also assessing response to therapy
    • MRI accurate in most
  • Lack of response to 1st line neoadjuvant chemo poor prognostic sign
  • Degree of involvement of axillary nodes post- neoadjuvant therapy is best predictor for subsequent relapse
  • Tumour grade and receptor IHC can change following neoadjuvant chemotherapy
  • Neoadjuvant treatment can clear involved nodes in up to 1/3 of patients
    • 50% of triple negative and 50% of HER2 (if tx with trastuzumab)
    • Only 10% of ER +ve disease

Neoadjuvant Options

Hormone recetor postive, HER2 negative

  • Less likely to respond to chemotherapy
    • Can shrink cancers but less likely to have cPR especially in luminal A
  • NSABP 18 Trial
    • 80% of patient had reduction in size of cancer and reduced node positivity
    • Increased the rate of BCS
  • Chemotherapy vs endocrine therapy
    • Less side effects in endocrine therapy
    • Time to response slower in endocrine therapy
      • Up to 3 months rx needed before response can be seen
      • Can lead to delay in switching rx if not working
    • Complete pathological response less likely with endocrine therapy
      • Gives different response pattern to chemo
        • Central scarring
      • Sparing the use of chemo now means it is available as option for adjuvant therapy
  • Regime selection
    • Pre menopausal → Chemotherapy
    • Post menopausal
      • Chemotherapy indicated in medically fit patients
      • In patients who are medically unfit for chemotherapy then endocrine therapy is an option
        • In postmenopausal women the evidence suggests similar response rates but less side effects with endocrine therapy although long term data not available
        • In a meta-analysis of 20 prospective, randomized clinical trials including 3490 patients in which at least one arm incorporated NET, neoadjuvant monotherapy with aromatase inhibitors (Ais) had a similar clinical response rate (odds ratio OR 1.08, 95% CI 0.50-2.35), BCS rate (OR 0.65, 95% CI 0.41-1.03), and radiologic response rate (OR 1.38, 95% CI 0.92-2.07) compared with neoadjuvant combination chemotherapy, but with lower toxicity. Ref
  • Chemotherapy
  • Endocrine therapy
    • Typically given in postmenopausal women only
      • Aromatase inhibitors suggested over Tamoxifen
        • AIs associated with a higher response rate
          • PROACT trial
            • Overall no significant difference in overall response rate between Anastrozole and Tamoxifen
            • In subset of patients who only received endocrine therapy who were not considered candidates for BCS at study entry, treatment with Anastrozoleimproved surgical options in 43 percent compared with 31 percent with Tamoxifen
          • ACOSOG Z1031 trial
            • Similar outcomes between different AIs

HER2 Positive

  • Combination of chemotherapy and Trastuzumab
  • Anthracycline based
    • Significant body of evidence suggesting efficacy
      • Reasonable option - although significant short- and long-term toxicities associated with anthracycline treatment - particularly cardiac
      • Most early studies assessing the benefit of the addition of trastuzumab to NACT in HER2-positive breast cancer employed anthracycline- and taxane-containing regimens, as did the initial randomized trials of the addition of trastuzumab to adjuvant chemotherapy, as this was the standard of care for high-risk breast cancer.
        • These studies suggest a pathologic complete response (pCR) rate approaching 50 percen
    • AC - Anthracycline Doxorubicin and Cyclophosphamide followed or proceed by Paclitaxel + Trastuzumab
  • Anthracycline-free

Triple negative

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