Targeted Therapy for HER-Positive Breast Cancer

• All patients with HER2 positive breast cancer:
  • Who require systemic therapy should complete one year of HER2-targeted therapy:
    • Including those who achieve pathologic complete response after neoadjuvant chemotherapy
  • One could also consider continuing adjuvant pertuzumab in addition to trastuzumab:
    • Based on results from the phase III Aphinity trial:
      • Although patients who received neoadjuvant chemotherapy were not included in this trial
  • For patients who have residual disease and do not achieve complete pathologic response at the time of surgery:
    • Completion of one year of T-DM 1(ado trastuzumab-emtansine)  decreased the risk of recurrence of invasive breast cancer or death:
      •  By 50% than with trastuzumab alone:
        • Based on results from KATHERINE trial:
          • The estimated percentage of patients who were free of invasive disease at 3 years was:
            • 88.3% in the T-DM1 group
            • 77.0% in the trastuzumab group
• Metastatic hormone receptor negative, HER positive breast cancer:
  • The CLEOPATRA study:
    • Showed that the combination of docetaxel, trastuzumab, and pertuzumab led to improved progression free survival (PFS) compared to docetaxel, trastuzumab, and placebo:
      • 18.5 months vs. 12.4 months
• Neoadjuvant chemotherapy (NAC):
  • Is appropriate for many patients with locally advanced breast cancer regardless of subtype:
    • Because a response may allow both:
      •  Less extensive surgery and improved surgical outcomes
    • Locally advanced disease is defined as stage III cancers, as well as the subset of IIB cancers with T3 disease
  • In addition, patients with earlier stage, HER2+ disease (stage I or II):
    • May also be candidates for neoadjuvant therapy, if one or more of the following criteria apply:
      • The patient desires breast-conserving surgery (BCS) but is not a candidate for BCS or is likely to have a suboptimal cosmetic outcome with BCS due to tumor location or size relative to the size of the patient’s breast, and may be a better candidate if neoadjuvant therapy decreases the extent of her tumor
      • The patient has limited axillary nodal involvement (N1), for which axillary lymph node dissection would be standard surgical management, but could be a candidate for sentinel lymph node sampling alone if converted to node-negative disease with neoadjuvant therapy
      • Surgery must be postponed awaiting:
        • consultation with plastic surgery regarding breast reconstruction
        • Results of genetic testing
        • Resolution of an intercurrent illness, including pregnancy, and the patient and treating clinicians do not wish to delay initiation of treatment
      • Postoperative treatment with ado-trastuzumab emtansine (T-DM1) would be considered if the patient were found to have residual invasive disease in the breast or axillary nodes following NAC with single or dual HER2-targeted therapy
• Pertuzumab:
  • Is a monoclonal antibody that binds to a different epitope on HER2 than trastuzumab:
    • Blocking the formation of HER2  : HER3 heterodimers:
      • Which is believed to be an important mechanism of resistance to trastuzumab
  • While single-agent pertuzumab has demonstrated antitumor activity in patients with HER2-positive metastatic disease who progressed on trastuzumab:
    • It is typically given in combination with trastuzumab to maintain suppression of signaling initiated by HER2 homodimers
  • In 2013, the FDA granted accelerated approval for the addition of pertuzumab to NACT and trastuzumab for patients with:
    • HER2+ locally advanced, inflammatory, or early-stage (either greater than 2 cm in diameter or node positive) breast cancer
  • I routinely recommend adding pertuzumab in patients receiving NACT and trastuzumab:
    • Given evidence that pertuzumab enhances locoregional responses:
      • Even though it increases the incidence and severity of treatment-related diarrhea as well as modestly increasing the frequency of hematologic toxicities
• NeoSphere trial:
  • In the phase II NeoSphere trial, 417 HER2+ patients received 12 weeks of neoadjuvant therapy:
    • Composed of either:
      • Four cycles of single-agent docetaxel with trastuzumab, pertuzumab, or both, or
      • The combination of trastuzumab and pertuzumab without concurrent docetaxel
      • After surgery, all patients received anthracycline-based adjuvant chemotherapy:
        • Those randomized to trastuzumab and pertuzumab alone also received adjuvant docetaxel)
      • Completed a year of treatment with trastuzumab

• Those randomly assigned to docetaxel with pertuzumab and trastuzumab had a higher pathologic complete response (pCR) rate (46%) compared with those receiving docetaxel with just trastuzumab (29%) or just pertuzumab (24%)
  • Patients receiving pertuzumab and trastuzumab without docetaxel had a pCR rate of 17%

• References:
  • Hayes DF. HER2 and breast cancer — a phenomenal success story. N Engl J Med. 2019;381(13):1284-1286.
  • Gianni L, Pienkowski T, Im Y-H, Tseng LM, Liu MC, Lluch A, et al. 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
  • von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant Pertuzumab and Trastuzumab in early HER2-positive breast cancer N Engl J Med. 2017;377(2):122-131.
  • von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.
  • Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New Engl J Med. 2012;366(2):109-119.
  • Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.

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