A neoadjuvant pathologic complete response (pCR)-adapted de-escalation strategy to omit chemotherapy in the adjuvant setting is clinically feasible and helps preserve health-related quality of life (HRQoL) in highly selected patients with low-risk HER2-positive early breast cancer, according to the phase II PHERGain-2 trial.
De-escalation strategy
PHERGain-2 included 396 treatment-naïve patients with small (5–30 mm), node-negative, early-stage HER2-positive (immunohistochemistry [IHC] 3+) breast cancer. The mean age of the patients was 55 years, 99.5 percent were female, 59.3 percent were postmenopausal, and 96.5 percent had an ECOG performance status of 0. At baseline, the median tumour size was 18 mm, 61.6 percent had T1b/T1c (>5 to ≤20 disease, and 72.7 percent had HR-positive tumours. [ESMO Breast 2026, abstract 214O]
All patients received eight cycles of fixed-dose subcutaneous trastuzumab–pertuzumab (600 mg + 1,200 mg loading dose, followed by 600 mg + 600 mg maintenance dose) every 3 weeks in the neoadjuvant setting. Surgery (breast-conserving or mastectomy with sentinel lymph node evaluation or axillary dissection) was performed within 4 weeks after completion of neoadjuvant treatment.
After surgery, adjuvant treatment was individualized based on pathologic findings. Patients with pCR received 10 cycles of trastuzumab–pertuzumab (maintenance dose) every 3 weeks (n=236). Those with residual invasive breast tumours with isolated tumour cells or micrometastases received 10 cycles of intravenous trastuzumab emtansine (3.6 mg/kg of body weight) every 3 weeks (n=148). Finally, those with locoregional nodal progression could receive optional chemotherapy before intravenous trastuzumab emtansine (n=7).
Adjuvant treatment continued until disease progression, unacceptable toxicity, withdrawal, or investigator decision. Patients with HR-positive tumours additionally received endocrine therapy in both the neoadjuvant and adjuvant settings. The median follow-up was 15.1 months.
Key findings
Following neoadjuvant treatment, 391 patients (98.7 percent) underwent surgery, and only two (0.5 percent) experienced disease progression on neoadjuvant treatment, reported senior investigator Dr Antonio Llombart-Cussac from Medica Scientia Innovation Research, Barcelona, Spain.
A total of 236 achieved pCR (59.6 percent). The rate of pCR did not differ by HR status (HR-negative: 63 percent; HR-positive: 58.3 percent) or by tumour size (T1 and T2: 59.6 percent for both), Llombart-Cussac noted.
The co-primary endpoint of a ≥10-percent HRQoL* decline at 1-year post-neoadjuvant therapy occurred in 42.8 percent of patients (95 percent confidence interval [CI], 36.9–48.8). The decline occurred more frequently among patients with HR-positive than those HR-negative tumours (45.2 percent vs 36.1 percent) and among patients who had residual disease vs those who achieved pCR after surgery (51.9 percent vs 37.2 percent).
The disparity in the incidence of ≥10-percent HRQoL decline, according to Llombart-Cussac, may be related to the addition of endocrine therapy to the neoadjuvant and adjuvant settings for patients with HR-positive disease, as well as the use of trastuzumab emtansine with or without chemotherapy in the adjuvant setting for patients who did not achieve pCR.
“The safety profile reported in this study was consistent with known toxicities of trastuzumab, pertuzumab, and T-DM1, largely attributable to the low chemotherapy exposure (only two patients out of 396 received chemotherapy),” Llombart-Cussac said.
Grade 3-5 treatment-related adverse events (TRAEs) occurred in 5.3 percent of patients, while serious TEAEs occurred in 1 percent. The most common TRAE was alanine aminotransferase elevation. A case of grade 5 pneumonitis related to trastuzumab emtansine was reported, and this resulted in death. There were no grade 4 TRAEs. Overall, TRAEs led to treatment discontinuation in 3.8 percent of patients.
Llombart-Cussac highlighted the remarkably high pCR rate of 59.6 percent in PHERGain-2, considering the inclusion of a significant proportion of patients with HR-positive tumours.
Pending 3-year recurrence-free interval outcomes, the findings demonstrate that “this response-adapted, chemotherapy-free strategy is clinically feasible and may support treatment individualization in selected low-risk patients,” he said.
Potentially practice-changing
Study discussant Dr Giampaolo Bianchini from IRCCS Ospedale San Raffaele, Milan, Italy, described PHERGain-2 as potentially practice-changing. “With this [response-adapted] strategy, the majority of patients could be treated with a chemo-free regimen … regardless of HR status.
“Although event-free survival (EFS) results are immature, there is a strong expectation of highly favourable EFS,” based on data from the initial PHERGain trial, wherein early metabolic imaging response and pCR to inform and individualize subsequent treatment in patients with stage I–IIIA invasive, operable HER2-positive breast cancer, Bianchini noted.
The approach used in PHERGain led to the omission of chemotherapy in approximately one-third of patients and resulted in a 3-year invasive disease-free survival of 94.8 percent. [Lancet 2024;403:1649-1659]