Neoadjuvant Chemotherapy with Trastuzumab with or without Concurrent Radiotherapy in HER2-Positive Inoperable Locally Advanced Breast Cancer: A Phase 2 Randomized Trial (NEOTRAC)

Abstract

Purpose/Objective(s)

The role of neoadjuvant concurrent chemoradiotherapy (NACCRT) with anti-HER2 therapy remains unexplored. We report the first phase 2 randomized controlled trial (RCT) evaluating whether adding NACCRT and trastuzumab improves pathological complete response (pCR) in HER2-positive inoperable locally advanced breast cancer (LABC).

Materials/Methods

Patients with newly diagnosed HER2-Positive inoperable LABC were randomized in a 1:1 ratio to receive either NACT with trastuzumab (Arm A) or NACCRT and trastuzumab (Arm B). Both arms received four cycles of Adriamycin and Cyclophosphamide (q 3 weekly), followed by four cycles of Paclitaxel (q 3 weekly) and nine weekly cycles of Trastuzumab. In Arm B, patients received concurrent radiotherapy (RT) to a total dose of 46 Gy to the breast and nodal areas along with paclitaxel and trastuzumab, followed by mastectomy. In contrast, patients in Arm A received postmastectomy RT to a total dose of 50 Gy after NACT and surgery. Adjuvant trastuzumab (q 3 weekly) was continued for one year in both arms. Primary endpoint was pCR while secondary endpoints included survival, toxicity, and treatment duration.

Results

Among 118 enrolled patients (Arm A: 62; Arm B: 56), 113 underwent surgery (Arm A: 58; Arm B: 55). Five patients (Arm A: 4; Arm B: 1) with complete clinical response (cCR) declined surgery. The median age was 50 years (range: 24–65), and all had stage III disease (IIIA: 40/118, [33.9%]; IIIB: 68/118 [57.6%]; IIIC: 10/118, [8.5%]). pCR rates were 46.6% (27/58) in Arm A versus 50.9% (28/55) in Arm B (P= 0.64), with no differences by subgroups (hormone receptor status, menopausal status, tumor size and stage grouping). At a median follow-up of 27 months, survival outcomes were similar. Event-free survival (EFS) was 81.0% (95% CI: 66.2–89.8) in Arm A versus 81.9% (65.2–91.1) in Arm B (P = 0.79). Overall survival (OS) was 93.0% (80.1–97.9) versus 95.1% (81.3–98.8) (P = 0.88) in Arms A and B respectively. NACCRT significantly reduced treatment duration (median 189 vs. 255 days, P < 0.00001). Surgical wound morbidity occurred in 6.9% (4/58) of Arm A versus 16.4% (9/55) of Arm B (P = 0.15). Grade 3 radiation dermatitis of 5.5% (3/55) and neutropenia 3.6% (2/55) were observed only in Arm B. No cardiac toxicity occurred. Among cCR patients declining surgery, 1/4 in Arm A progressed, while all others (3/4 Arm A, 1/1 Arm B) remained disease-free.

Conclusion

To our knowledge, this is the first RCT of NACCRT with trastuzumab. While pCR was higher with NACCRT, the difference was not significant. NACCRT was well tolerated, showed no added cardiac toxicity, and significantly reduced treatment duration, potentially lowering hospital visits and income loss. It may be a feasible option for patients seeking shorter, effective treatment. Further studies are warranted to explore whether the benefit of shortened overall treatment duration with NACCRT can be extended to the adjuvant setting in breast cancer management.