Optimizing the adjuvant chemotherapy for HER2-positive early breast cancer

Human epidermal growth factor 2 (HER2)-positive breast cancer accounts for approximately 15% of all breast cancers (1). Its prognosis has been improved since trastuzumab, the first HER2-targeted antibody, was introduced in 1998 (2). In the perioperative settings, the dual HER2-targeted therapy, combination of pertuzumab and trastuzumab plus docetaxel, has been shown to improve invasive disease-free survival (IDFS) and pathological complete response (pCR) rates (3,4). However, the benefits of dual HER2-targeted therapy for early breast cancer with low risk of recurrence, such as small node-negative (N0) tumors, were not clear. Moreover, the dual HER2-targeted therapy is associated with toxicities which affect the patients’ quality of life, such as peripheral neuropathy, alopecia and myalgia. After the APT (Adjuvant Paclitaxel and Trastuzumab) trial showed successful de-escalation of adjuvant chemotherapy to trastuzumab plus paclitaxel for N0 or N1 HER2-positive early breast cancer with tumor size <3 cm (5), there is growing concerns in overtreatment given the toxicities of anti-HER2 therapies with taxane.

One of the strategies to reduce toxicities of the dual HER2-targeted therapy is switching to antibody-drug conjugates. In the phase 2 PREDIX HER2 trial, trastuzumab emtansine (T-DM1) was compared to combination of pertuzumab and trastuzumab plus docetaxel as a neoadjuvant therapy for HER2-positive breast cancers with tumor size >2 cm and/or lymph node metastases. T-DM1 group showed similar pCR rate compared to the standard treatment group (45.5% vs. 43.9%, P=0.82) with less toxicity (6). Meanwhile, the phase 3 KRISTINE trial [A Phase III Study of Neoadjuvant and Adjuvant Treatment With Trastuzumab Emtansine (T-DM1) Plus Pertuzumab vs. Docetaxel, Carboplatin, Trastuzumab and Pertuzumab (TCHP) in HER2-Positive Breast Cancer] compared T-DM1 plus pertuzumab with docetaxel, carboplatin, and trastuzumab plus pertuzumab for neoadjuvant chemotherapy in patients with HER2-positive stage II or III breast cancer (7). Though grade 3–4 adverse events were significantly fewer in T-DM1 plus pertuzumab group than in chemotherapy group (13% vs. 64%), the pCR rate was superior in chemotherapy group compared to that in T-DM1 plus pertuzumab group (55.7% vs. 44.4%, P=0.016). The phase 3 KAITLINE trial evaluated adjuvant T-DM1 plus pertuzumab after anthracycline-based regimen compared to taxane plus trastuzumab plus pertuzumab for node-positive, or node-negative with tumor size >2 cm HER2-positive breast cancer, which showed no significant IDFS difference between the two groups (8). These results suggested that replacing the conventional chemotherapy with T-DM1 is not recommended, and dual HER2-targeted therapy remains the standard treatment for HER2-positive stage II or III breast cancer. Then, what about early breast cancer with a low risk of recurrence?

The phase II ATEMPT (Adjuvant Trastuzumab Emtansine vs. Paclitaxel Plus Trastuzumab for Stage I HER2-Positive Breast Cancer) trial aimed to evaluate the efficacy of T-DM1 among patients with pathologic stage I HER2-positive breast cancer compared to APT regimen (9). After surgery, the eligible patients were randomly assigned in a 3:1 ratio to receive T-DM1 or trastuzumab plus paclitaxel. The incidence of clinically relevant toxicities and IDFS were set as the coprimary end points. A total of 512 patients were included; 384 were assigned to receive T-DM1 and 128 received trastuzumab plus paclitaxel. Patients with nodal micro metastasis were included 4% in this study. A total of 11 IDFS events were observed and the 5-year IDFS was 97.0% [95% confidence interval (CI): 95.2–98.7%] in the T-DM1 arm. Among the 11 IDFS events, distant recurrences were only seen in three patients. Though the efficacy of trastuzumab plus paclitaxel was not powered to be evaluated, 9 IDFS events were observed in the control arm and the 5-year IDFS was 91.1% (95% CI: 85.7–96.8%). These results imply the potential of T-DM1 as an alternative choice to APT regimen for the adjuvant chemotherapy of HER2-positive early breast cancer, though several concerns still remain.

The ATEMPT trial reported a small number of recurrences, raising concerns about which patients are able to receive the de-escalation therapy without increasing the risk of recurrence. Considering the potential negative effects of the heterogeneity of HER2 expression on the efficacy of T-DM1 (10), the authors conducted single-cell analysis using evaluable tissues from 52 patients among the participants of ATEMPT trial, which showed no significant association between HER2 genetic heterogeneity and recurrence. Contrary, recurrence risk appeared to be associated with the results of HER2DX score, a genomic tool measuring 27 genes of HER2-positive breast cancer. Further prospective researches are needed; however, classification of recurrence risk based on genetic alternations would be a reasonable strategy to optimize the de-escalate adjuvant chemotherapy for HER2-positive early breast cancer.

Another antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), was currently approved for HER2-positive breast cancer. The phase 3 DESTINY-Breast 03 trial has showed the superior survival benefits of T-DXd compared to T-DM1 in the patients with HER2-positive advanced breast cancer (11). As adjuvant chemotherapy for HER2-positive early breast cancer, the phase 3 DESTINY-Breast 05 trial (NCT04622319) is ongoing to compare the efficacy of T-DXd with T-DM1 for residual invasive disease after neoadjuvant chemotherapy. Whether adjuvant T-DXd can reduce toxicities without increasing recurrence risks would be the next interests of adjuvant chemotherapy for HER2-positive early breast cancer.

In conclusion, the phase 2 ATEMPT trial suggested that adjuvant T-DM1 for 1 year reduces toxicities without compromising IDFS among HER2-positive stage I breast cancer. Further research is expected to make adjuvant anti HER2 treatment for early breast cancer less toxicities and more effective for all patients.

Corresponding Article

Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT

• 
  Tarantino, Paolo MD^4,
• 
  Tayob, Nabihah PhD⁵
• 
  Villacampa, Guillermo PhD^7,
• Dang, Chau MD^8,
• Yardley, Denise A. MD^9,
• 
  Isakoff, Steven J. MD, PhD^10,
• Valero, Vicente MD^11,
• Faggen, Meredith MD¹
• 
  Mulvey, Therese MD^10,
• 
  Bose, Ron MD, PhD^12,
• Weckstein, Douglas MD¹³
• 
  Wolff, Antonio C. MD^14,
• 
  Reeder-Hayes, Katherine MD, MBA, MSc^15,
• 
  Rugo, Hope S. MD^16,
• Ramaswamy, Bhuvaneswari MD^17,
• 
  Zuckerman, Dan MD^18,
• Hart, Lowell MD^19,
• 
  Gadi, Vijayakrishna K. MD, PhD^20,
• Constantine, Michael MD¹
• 
  Cheng, Kit MD^21,
• Garrett, Audrey Merrill MD²²
• 
  Marcom, P. Kelly MD^23,
• 
  Albain, Kathy MD^24,
• DeFusco, Patricia MD^25,
• 
  Tung, Nadine MD^26,
• Ardman, Blair MD²⁷
• 
  Nanda, Rita MD^28,
• 
  Jankowitz, Rachel C. MD^29,
• 
  Rimawi, Mothaffar MD^30,
• 
  Abramson, Vandana MD^31,
• Pohlmann, Paula R. MD, PhD, MSc^32,
• 
  Van Poznak, Catherine MD^33,
• 
  Forero-Torres, Andres MD^34,
• 
  Liu, Minetta C. MD^35,
• 
  Ruddy, Kathryn J. MD^36,
• Waks, Adrienne G. MD^3,
• DeMeo, Michelle BS²
• 
  Burstein, Harold J. MD, PhD^3,
• 
  Partridge, Ann H. MD, MPH^3,
• Dell'Orto, Patrizia ScD^37,
• Russo, Leila MD³⁷
• 
  Krause, Emma PhD^38,
• Newhouse, Daniel J. PhD^39,
• 
  Kurt, Busem Binboğa MD²
• 
  Mittendorf, Elizabeth A. MD, PhD, MHCM^40,
• 
  Schneider, Bryan MD^41,
• 
  Prat, Aleix MD, PhD^43,
• 
  Winer, Eric P. MD^44,
• 
  Krop, Ian E. MD, PhD^44,
• 
  Tolaney, Sara M. MD, MPH^3,,
• on behalf of the Consortium of the TBCRC Translational Investigators

Journal of Clinical Oncology 42(31):p 3652-3665, November 1, 2024. | DOI: 10.1200/JCO.23.02170