Risk-Adaptive Approaches Offer Safer, Effective Strategies for Early-Stage HER2+ Breast Cancer

The integration of HER2-targeted therapies into the treatment paradigm for patients with early-stage breast cancer, specifically the standard trastuzumab (Herceptin), has shifted focus away from whether patients should receive to how and when they should receive treatment with these agents. With 4 agents approved for this setting—trastuzumab, pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla; T-DM1), and neratinib (Nerlynx)—risk-adapted approaches for this patient population may further improve outcomes and reduce the risk of recurrence, said Sara A. Hurvitz, MD, in a presentation at the 39th Annual Miami Breast Cancer Conference®.¹

“Despite successes [in the trastuzumab-era], it’s important to note that recurrences do happen, and they may occur late. Up to 20% of patients will experience a disease recurrence by year 10 despite [having received] trastuzumab-based therapy,” said Hurvitz, who is an associate professor at the David Geffen School of Medicine at University of California, Los Angeles (UCLA), medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit, codirector of the Santa Monica-UCLA Outpatient Oncology Practices, and director of the Breast Cancer Clinical Trials Program at UCLA. “The question is: How do we identify patients who need more [therapy] and how do we know when enough is enough?”

Hurvitz explained that the size of a patient’s tumor, as well as the timing of systemic therapy—either in the neoadjuvant or adjuvant setting—does not appear to be a contributing factor for determining treatment outcomes. “We know that giving systemic therapy before surgery yields the same long-term outcomes as giving it after surgery. Even [those with] very small tumors benefit from a HER2-targeted therapy approach,” Hurvitz said.

What does matter, according to Hurvitz, is use of response-guided approaches for these patients. “A response type approach allows us to start with a less toxic therapy and switch to a severe regimen if the tumor does not respond appropriately. We now know that residual cancer after neoadjuvant systemic therapy is prognostic and predictive and predictive of benefit from adjuvant T-DM1.”

For example, Hurvitz pointed to the practice-changing data from the KATHERINE trial (NCT01772472), which showed that patients with HER2-positive disease who had residual disease following neoadjuvant therapy and received T-DM1 in the adjuvant setting had a 50% reduction in the risk of death compared with those who received adjuvant trastuzumab.² Specifically, the estimated 3-year invasive disease-free survival (iDFS) rate among the 743 patients who received adjuvant T-DM1 was 88.3% vs 77.0% among those who received adjuvant trastuzumab (n = 743; HR, 0.50; 95% CI, 0.39-0.64; P < .001). The 3-year freedom from distant recurrence rates were 89.7% vs 83.0%, respectively.

The benefit extended to those patients with clinically small tumors. Those with stage ct1 tumors who received T-DM1 (n = 99) had a 3-year iDFS rate of 94.8% vs 83.4% for those treated with trastuzumab (n = 81; HR, 0.33; 95% CI, 0.13-0.88). Among those with stage ct2 tumors, those who received T-DM1 (n = 365) had a 3-year iDFS rate of 90.4% vs 82.0% among those who received trastuzumab (n = 389; HR, 0.52; 95% CI, 0.35-0.78). Further, an improved benefit was observed with T-DM1 vs trastuzumab among those with lymph node–negative disease (HR, 0.32; 95% CI, 0.17-0.61).²

In contrast, data from nonselected trials, which included patients with both high-risk and low-risk disease, such as the APHINITY trial (NCT01358877), demonstrate the importance of selecting populations who would benefit from additional treatment. A small benefit was observed among those treated with the HER2-directed therapy pertuzumab vs placebo (HR, 0.85; 95% CI, 0.67-1.07), which Hurvitz noted might not be enough to justify the associated toxicity with the regimen for patients.³

The neoadjuvant setting is also where clinicians can omit the use of riskier regimens, such as the use of anthracycline-based therapy, Hurvitz said. For patients with stage II or stage III tumors, pathological complete response (pCR) has become a standard measure to individualizing therapy in the neoadjuvant setting. For patients with early-stage disease, Hurvitz highlighted that a similar tactic can be applied to mitigate risk.

“Some of the first data suggesting a benefit from the use on nonanthracycline-based regimen came from TRYPHAENA [NCT00976989], a phase 2, randomized trial which [evaluated] the cardiac safety of regimens including the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen vs the anthracycline-based regimen FEC/HP [5-fluorouracil, epirubicin, cyclophosphamide/trastuzumab plus pertuzumab] followed by THP [docetaxel, trastuzumab, pertuzumab],” Hurvitz said. The pCR rate was higher among those who received the nonanthracycline regimen vs those who did not, and the disease-free and progression-free survival rates were similar between the arms.^4,5

Results of several neoadjuvant studies using adaptative strategies with a trastuzumab/pertuzumab as a backbone showed that pCR rates above 50% for patients with early-stage disease. Recommendations in the National Comprehensive Cancer Network Guidelines reflect the trend in comparable data with fewer adverse effects listing nonanthracycline regimens—paclitaxel plus trastuzumab, TCH, or TCHP—as preferred treatment options for patients with HER2-positive disease in the preoperative and adjuvant settings.⁶ “The anthracycline-based regimens were moved to the ‘useful in certain circumstances’ category,” Hurvitz noted.

In terms of moving the needle toward less treatment, Hurvitz reviewed data from trials evaluating the adjuvant trastuzumab in patients with stage I disease as a way to de-escalate chemotherapy therapy and preserve patient quality of life. The APT trial (NCT00542451) evaluated trastuzumab plus paclitaxel for 12 weeks followed by single-agent trastuzumab for
 9 months in 410 patients with HER2-positive tumors measuring 3 cm or less.⁷ At a median follow-up of 7.5 years, the 7-year DFS rate was 93.3% (95% CI, 90.4%-96.2%). Despite the success at 7 years, Hurvitz noted that recurrences are still occurring, but that this treatment may be useful in the neoadjuvant setting to help patients who might be at a higher risk
of recurrence.

In patients with estrogen receptor–positive, HER2-positive breast cancer, de-escalation chemotherapy vs endocrine therapy plus pertuzumab plus trastuzumab was evaluated in the phase 2 WSG TP-II trial (NCT03272477). pCR was observed in 24% (95% CI, 16%-34%) of patients who received endocrine therapy (n = 96) vs 57% (95% CI, 47%-67%) of those treated with de-escalated paclitaxel (n = 102; OR, 0.24; 95% CI, 0.0-0.46; P < .001).⁸

A similar study was designed and executed for patients with hormone receptor–negative, HER2-positive disease. In the phase 2 WSG-ADAPT HER2+/HR− trial (NCT01779206), investigators evaluated the efficacy of trastuzumab plus pertuzumab with or without paclitaxel in the neoadjuvant setting. The pCR rate among 42 treated patients in either arm was 90.5% with the addition of paclitaxel compared with 36.3% with trastuzumab and pertuzumab alone.⁹

As for whether chemotherapy can be omitted entirely, Hurvitz said, “Yes, you can do it and achieve CRs without the use of chemotherapy although the pCR rates are fairly low.” Hurvitz added that she would not advocate for this approach outside of a clinical trial. “I do advocate for trials that continue to push the envelope and do de-escalation for lower-risk patients perhaps those with hormone receptor–positive, node-negative tumors.”

References

1. Hurvitz SA. Risk-adapted treatment for early-stage HER2+ breast cancer. Presented at: 39th Annual Miami Breast Cancer Conference®. March 3-6, 2022; Miami Beach, FL.
2. von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
3. Piccart M, Procter M, Fumagalli D, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years’ follow-up. J Clin Oncol. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204
4. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284. doi:10.1093/annonc/mdt182
5. Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018;89:27-35. doi:10.1016/j.ejca.2017.10.021
6. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2022. Accessed March 5, 2022.https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
7. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2019;37(22):1868-1875. doi:10.1200/JCO.19.00066
8. Gluz O, Nitz U, Christgen M, et al. De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): first efficacy results from the neoadjuvant WSG-TP-II study. J Clin Oncol. 2020;38(suppl 15):515. doi:10.1200/JCO.2020.38.15_suppl.515
9. Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol. 2017;28(11):2768-2772. doi:10.1093/annonc/mdx494