Adjuvant Chemotherapy for Triple Negative Breast Cancer

  • Algorithm for Adjuvant Therapy (AC) in TNBC:
    • For histologic types:
      • Ductal
      • Lobular
      • Mixed
      • Metaplastic
    • For pT1, T2, or T3 and pN0 or pN1mi (≤ 2 mm axillary nodal metastasis), adjuvant systemic treatment depends on tumor size:
      • For T1a (T ≤ 0.5 cm including microinvasive) and pN0-NO adjuvant therapy, however, if pN1mi:
        • Adjuvant therapy should be considered
      • For T1b (T > 0.5 cm and ≤ 1.0 cm), pN0 or pN1mi:
        • Adjuvant therapy should be considered
      • For tumors greater than 1 cm, N0 or N1mi:
        • Chemotherapy should be given
      • For node-positive disease (one or more metastases ≥ 2 mm) to one or more axillary lymph nodes:
        • AC should be given
  • Standard Adjuvant Systemic Chemotherapy for TNBC:
    • Current AC for TNBC does not differ according to subtype
  • Preferred regimens are:
    • Dose-dense AC (doxorubicin / cyclophosphamide) followed by paclitaxel every 2 weeks
    • Dose-dense AC followed by weekly paclitaxel
    • TC (docetaxel and cyclophosphamide)
  • Other acceptable adjuvant therapy regimens as per NCCN guidelines are:
    • Dose-dense AC (doxorubicin / cyclophosphamide)
    • AC (doxorubicin / cyclophosphamide) every 3 weeks
    • Cyclophosphamide / methotrexate / fluorouracil
    • AC followed by docetaxel every 3 weeks
    • AC followed by weekly paclitaxel
    • Epirubicin / cyclophosphamide
    • TAC (docetaxel / doxorubicin / cyclophosphamide)
  • High-risk triple-negative patients are, in general:
    • Treated with an anthracycline and a taxane-containing regimen
  • Emerging concepts in systemic therapy for TNBC – Precision Medicine:
    • The considerable overlap of the BRCA1 tumor phenotype and TNBC:
      • Has led investigators to take advantage of TNBC BRCA-ness when considering chemotherapy regimens
    • The DNA repair defects characteristic of BRCA1-deficient cells:
      • Confer sensitivity to poly (adenosine diphosphate ribose) polymerase 1 (PARP) inhibition
      • Platinum salts:
        • Such as carboplatin and cisplatin:
          • Cause DNA cross-link strand breaks and thus should be effective in BRCA-mutated calls and TNBC:
            • Which are deficient in homologous DNA repair mechanisms
  • Consideration should be given for neoadyuvant chemotherapy (NAC) for:
    • Stages IIA, IIB, and IIIA and if the patient fulfills criteria for breast-conserving surgery apart from tumor size
  • The NCCN guidelines recommend:
    • The same NAC regimens for TNBC as for adjuvant treatment
  • Pathologic complete response (pCR) rates:
    • For TNBC are higher (22% to 44%) than for non-TNBC (6% to 11%)
  • Residual disease following NAC:
    • Portends a worse prognosis than a pCR
  • Response to neoadjuvant therapy (adriamycin-, cytoxan-, taxol-containing regimens) differs according to intrinsic subtype:
    • Masuda and colleagues noted a pCR of 28% overall:
      • However, when looked at by subtype:
        • BL1 subtype has a pCR of 52% versus:
          • BL2 0%
          • LAR 10%
          • MSL (23%)
  • TNBC subtype is an independent predictor of pCR following NAC:
  • Tsai and colleagues determined that residual nodal disease post-NAC for TNBC was associated with an unfavorable outcome:
    • They calculated the lymph node ratio (LNR) and the proportion of positive nodes over the number excised, following NAC according to molecular subtype:
      • Patients with a low LNR (≤ 0.2) had a prolonged DFS compared with those with a high (> 0.65) LNR
  • Patients with TNBC:
    • Have higher pCR rates in the axilla following NAC than patients with hormone receptor-positive cancers:
      • 49.4% versus 21.1%
  • Further, a pCR determined by the sentinel node biopsy in the axilla may reduce the need for full axillary dissection in selected patients who achieve the pCR:
    • Axillary downstaging to reduce the extent of axillary node dissection with NAC is an emerging paradigm
  • Despite the relative chemosensitivity of TNBC:
    • Early relapse is common:
      • Leading to the term:
        • Triple-negative paradox
    • TNBC tumors show increased rates of pCR to NAC:
      • But have lower DFS and overall survival (OS) compared with other subtypes
  • It has been postulated that the triple-negative paradox:
    • Is due to differing pCR rates and higher likelihood of relapse in patients who do not achieve pCR
  • Swisher and colleagues found that failure to achieve a pCR (in both the breast and axilla) following NAC:
    • Was a significant adverse feature for patients with TNBC tumors
    • With a median follow-up of 4.6 years:
      • Those with a pCR the locoregional recurrence-free survival was:
        • 98.6% versus 89.9% for those who did not achieve pCR (p = .007)
  • For TNBC patients having residual disease following NAC:
    • The use of AC following surgery has been associated with an improvement in survival
  • The CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy) trial:
    • Was designed to study the effect of adjuvant capecitabine on patients with TNBC who did not achieve pCR following NAC
    • Women in the capecitabine group:
      • Had better 2-year:
        • DFS:
          • 82.8% versus 74.0%
        • OS:
          • 94% versus 89.2%
  • In an ongoing clinical trial (SWOG 1418):
    • The role of pembrolizumab (an immune checkpoint inhibitor) in patients with residual disease after NAC is being investigated
  • Two landmark trials have shown the efficacy of platinum salts when added to NAC regimens for TNBC:
    • The GeparSixto trial:
      • Compared paclitaxel, doxorubicin, and bevacizumab (Avastin) with or without carboplatin
      • In the TNBC subset:
        • pCR improved from 37.9% to 58.7% with the addition of carboplatin
    • In the Cancer and Leukemia Group B 40603 trial:
      • Patients received paclitaxel 80 mg/m2 once per week for 12 weeks followed by doxorubicin plus cyclophosphamide once every 2 weeks for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and / or bevacizumab 10 mg/kg once every 2 weeks for nine cycles
      • The addition of either carboplatin (60% versus 44%; p = .0018) or bevacizumab (59% versus 48%; p = .0089) significantly increased pCR in the breast:
      • Whereas only carboplatin (54% versus 41%; p = .0029) significantly raised pCR in both and axilla
  • In a meta-analysis of eight platinum-based therapy trials for TNBC:
    • Tian and colleagues concluded that both pCR and overall response rate:
      • Were significantly higher for platinum-based regimens
  • In the I-SPY 2 trial:
    • A phase 2, multicenter, adaptively randomized trial:
      • Multiple experimental regimens in combination with standard NAC were screened
    • Seventy-two patients with TNBC were randomly assigned to receive veliparib (a PARP inhibitor), carboplatin, and standard therapy, and 44 patients were concurrently assigned to receive control therapy
    • The investigators found the estimated rates of pathologic complete response in the triple-negative population at the completion of chemotherapy were:
      • 51% in the veliparib-carboplatin group versus 26% in the control group
      • They concluded that veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial for TNBC

#Arrangoiz #CancerSurgeon #BreastSurgeon #SurgicalOncologist #ComplexSurgicalOncology #BreastCancer #TripleNegativeBreastCancer #TNBC #Miami #Mexico #Teacher #Surgeon #MountSinaiMedicalCenter #MSMC

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