Tailoring Therapy in Breast Cancer Proves to Be an Elusive Goal

Historically, the diagnosis of HER2-positive breast cancer was associated with an increased risk of recurrence and death from the disease, but with the emergence of effective chemotherapy and targeted treatment against HER2, that prognosis has significantly improved.

“We have come a long way over the last decade or so in treating early-stage HER2-positive breast cancer,” Sara M. Tolaney, MD, MPH, associate professor of medicine at Harvard Medical School, and chief of the Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancer at Dana-Farber Cancer Institute, both in Boston, Massachusetts, said. “We have come to understand that we can treat a patient in the preoperative setting, measure their response to treatment, and then adapt treatment after surgery based on that response,” Tolaney, who is also associate director at the Susan F. Smith Center for Women’s Cancer, told Targeted Therapies in Oncology (TTO), during an interview.

Sara M. Tolaney, MD, MPH

Associate Professor of Medicine

Harvard Medical School

Chief, Division of Breast Oncology

Associate Director Susan F. Smith Center for Women’s Cancers

Dana-Farber Cancer Institute

Boston, MA

Tolaney will present “Early-Stage HER2- Positive Breast Cancer” at the 21st Annual School of Breast Oncology, and previewed the topic with TTO prior to the conference, which will be held in Atlanta, Georgia, November 2 to 4, 2023.

The combination of docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta) is an established regimen that has led to improved overall survival in patients with HER2-positive metastatic breast cancer.^1,2 These encouraging findings led to the evaluation of dual blockade therapy in both the neoadjuvant and adjuvant settings.

Dual Blockade Therapy

“We learned from trials, such as NeoSphere [NCT00545688] and TRYPHAENA [NCT00976989], that adding pertuzumab to chemotherapy has improved rates of pathologic complete response [pCR],” Tolaney said.^3,4

In the NeoSphere trial, patients were randomly assigned to 4 groups: group A received trastuzumab plus docetaxel; group B received pertuzumab and trastuzumab plus docetaxel; group C received pertuzumab and trastuzumab; and group D received pertuzumab plus docetaxel. Investigators reported that patients in group B had an improved pCR compared with patients in group A.³

The cardiac safety of combining pertuzumab with trastuzumab and chemotherapy was evaluated in the TRYPHAENA trial.⁴ In the trial, 250 patients with operable, locally advanced, or inflammatory breast cancer were randomly assigned 1:1:1 into 3 groups: arm A (5-fluorouracil, epirubicin, cyclophosphamide plus trastuzumab and pertuzumab for 3 cycles, followed by docetaxel plus trastuzumab and pertuzumab for cycles); arm B (5-fluorouracil, epirubicin, cyclophosphamide for 3 cycles, followed by docetaxel plus trastuzumab and pertuzumab for 3 cycles); or arm C (docetaxel plus carboplatin plus trastuzumab plus pertuzumab for 6 cycles).⁴

Investigators observed low rates of symptomatic left ventricular systolic dysfunction when pertuzumab and trastuzumab were used in combination.⁴

“But this led to further evaluation of pertuzumab and its effect on improving outcomes,” Tolaney added. “[Data from] the APHINITY trial [NCT01358877] confirmed the invasive disease–free survival of [patients who received] the combination of pertuzumab and standard adjuvant therapy.”⁵

In APHINITY, 4805 patients with node-positive or high-risk node-negative breast cancer were randomly assigned to receive either chemotherapy plus 1 year of trastuzumab and placebo or 1 year of trastuzumab and pertuzumab.⁵

With over 8 years of follow-up, improvement in overall survival has not been observed, Tolaney said. “The benefits of adding pertuzumab were restricted to those patients with node-positive disease, with minimal benefit observed from adding pertuzumab in patients with node-negative disease,” she explained.

De-escalation Strategies

With the extensive armamentarium available in breast cancer, and especially with the emergence of multiple new HER2- directed agents, a rationale is emerging that focuses on de-escalation. “Can we achieve the same efficacy, but decreased toxicity, if we tailor therapy to the individual patient?” Tolaney asked. “For example, when treating small HER2-positive cancers, we have learned that [by] that administering an abbreviated amount of chemotherapy—that is, 12 weeks of paclitaxel—we can achieve important outcomes,” Tolaney said. Interest in following a de-escalation strategy may be met with mixed enthusiasm, however. Because current regimens for patients with HR-positive, HER2-positive early-stage breast cancer are well tolerated with good outcomes, oncologists and their patients may not embrace this rationale.⁶

Tolaney highlighted data from the CompassHER2-pCR trial (NCT04266249), which is evaluating how well paclitaxel, trastuzumab, and pertuzumab work in eliminating further chemotherapy after surgery in patients with HER2-positive stage II-IIIa breast cancer who have no cancer remaining at surgery after preoperative chemotherapy and HER2-targeted therapy.

In this ongoing trial, eligible patients should have an ECOG Performance Status Scale score of 0 or 1 with histologically confirmed HER2-positive primary invasive breast cancer that is determined by local testing. In addition, the patient’s tumor should have either a HER2 immunohistochemistry result of 3+ or HER2-CEP17 ratio greater than 2.

Tumor Biology vs Size of Tumor

Another topic that is undergoing debate in the HER2-positive disease setting is the role of tumor biology vs size of tumor. Tolaney said that patients who achieve a pCR to HER2-directed therapy generally have a good response that leads to positive outcomes.

“But not all pCRs are the same,” cautioned Tolaney. When comparing a patient with a large tumor with multiple lymph node involvement who achieves pCR after therapy with a patient who has a small cancer with limited lymph node involvement up front, she said, the patient with the higher clinical anatomic risk usually has a higher risk of recurrence.

“That to me suggests that biology [is a bigger driver],” Tolaney said. “The patient’s clinical anatomic risk puts them at still higher risk of recurrence even if their tumor responded to therapy and they achieved a pCR. I think, ultimately, we will have to integrate both biology and clinical risk when trying to understand how to tailor therapy when we derive biomarker-driven approaches,” Tolaney said.

Despite the advances and successes in improving outcomes, many unmet needs remain, Tolaney said. Giving too much therapy or too little therapy is an ongoing challenge, so efforts to optimize treatment and improve personalized care continue to be explored. “We’ll continue to see advances emerge and evolve as we learn more about this disease,” Tolaney concluded.

REFERENCES:

1. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216

2. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513

3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32. doi:10.1016/S1470-2045(11)70336-9

4. 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;89:2735. doi:10.1016/j.ejca.2017.10.021

5. 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

6. File D, Curigliano G, Carey LA. Escalating and de-escalating therapy for early-stage HER2-positive breast cancer. Am Soc Clin Oncol Educ Book. 2020;40:1-11. doi:10.1200/ EDBK_100023