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