Abstract

Introduction:

The role of trastuzumab in the neoadjuvant setting has been established by multiple large randomized trials. However, there are limited data on the efficacy and survival outcomes of the FinHer regimen in the neoadjuvant setting for the treatment of HER2-positive breast cancer in the South Indian population.

Methods:

This retrospective audit included patients with locally advanced HER2-positive breast cancer who received neoadjuvant chemotherapy with a short course of trastuzumab (nine weekly doses) following the FinHer protocol in a resource-limited setting. The primary endpoint of the study was pathological complete response (pCR). Secondary endpoints included disease-free survival (DFS) and overall survival (OS) at 5 years. The primary study population comprised stage III patients, while patients with oligometastatic disease were included as an exploratory cohort.

Results:

This retrospective audit included 100 patients. Of these, 76 patients had stage III disease and 24 had oligometastatic disease. The pCR rate was 30% following the neoadjuvant FinHer protocol. Estrogen receptor (ER) and progesterone receptor (PR) positivity were associated with decreased pCR rates, which were statistically significant (p = 0.002). Patients with the HER2-enriched subtype (47%) achieved higher pCR rates compared to those with the luminal B HER2-positive subtype (21.2%), with a statistically significant p-value (p = 0.008). On univariate and multivariate analyses, stage was the only significant predictor of DFS (p = 0.003) and OS (p = 0.002). Stage III disease remained independently associated with improved survival outcomes compared to oligometastatic disease [OS: hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.18–0.70, p = 0.003; DFS: HR 0.40, 95% CI 0.21–0.76, p = 0.005]. Achievement of pCR was associated with a numerically lower risk of death and recurrence (OS: HR 0.56, 95% CI 0.24–1.30; DFS: HR 0.51, 95% CI 0.22–1.16).

Conclusion:

The neoadjuvant FinHer protocol resulted in a pCR rate of 30% in locally advanced HER2-positive breast cancer. ER/PR positivity was associated with decreased pCR rates. Achievement of pCR was associated with a numerically lower risk of death and recurrence. Stage III disease remained independently associated with improved survival outcomes compared to oligometastatic disease.

Introduction

The advent of trastuzumab has revolutionized the treatment of breast cancer, and it is currently used in the neoadjuvant, adjuvant, and metastatic settings for patients with HER2-positive breast cancer (1). The recommended duration of trastuzumab therapy in breast cancer treatment, whether in the adjuvant or neoadjuvant setting, is a total of 17 cycles. However, several trials have explored the use of trastuzumab in abbreviated regimens (2–4). The FinHer trial paved the way for multiple studies evaluating chemotherapy combined with shorter courses of trastuzumab, with conflicting results regarding survival compared to longer durations of trastuzumab treatment (5). Meta-analyses have suggested that shorter courses of trastuzumab may be an alternative for patients with lower-risk disease and for those with cardiac dysfunction (6). Shorter courses of trastuzumab may be an attractive option for reducing the financial burden of treatment, decreasing trastuzumab-related toxicities, and significantly shortening the duration of therapy, particularly in middle- and low-income countries in Asia. At our center, many patients were unable to afford 1 year of adjuvant trastuzumab during that period. Consequently, the FinHer protocol was adopted for patients with HER2-positive breast cancer in both adjuvant and neoadjuvant settings. The role of trastuzumab in the neoadjuvant setting has been established by multiple large randomized trials (7–11). However, there is limited evidence regarding the efficacy and survival outcomes of shorter courses of trastuzumab in the neoadjuvant treatment of HER2-positive breast cancer. The clinico-epidemiological pattern of HER2-positive breast cancer in Asian populations differs from that in Western populations, with younger age at presentation and more advanced-stage disease being more common (12). This places a substantial financial burden on both families and national healthcare systems. Therefore, the aim of this study was to evaluate the effectiveness of the FinHer protocol as a neoadjuvant treatment in terms of pathological response and 5-year survival outcomes among patients with HER2-positive breast cancer in a resource-limited setting.

Methods

This study was a single-center, retrospective audit of consecutively treated patients with HER2-positive locally advanced breast cancer who received neoadjuvant chemotherapy with a short course of nine weekly trastuzumab cycles (FinHer protocol) at the Breast Clinic, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, between 1 January 2017 and 30 December 2018. This research audit was approved by the Institutional Review Board (IRB No: 12/2019/02).

The inclusion criteria comprised all newly diagnosed, consecutively treated patients with locally advanced HER2-positive breast cancer who received neoadjuvant chemotherapy with a short course of nine weekly trastuzumab cycles. Patients aged >14 years and <70 years were included. Only stage III patients and those with oligometastatic disease were eligible. The primary study population consisted of stage III patients, while patients with oligometastatic disease were included for exploratory analysis. Patients with stage I and II disease, including those classified as high risk, were excluded. The exclusion of high-risk patients was based on tumor board decisions, as the study primarily focused on locally advanced breast cancer in the neoadjuvant setting. Patients with ≤5 metastases in total and metastases measuring ≤5 cm, amenable to local therapy, were classified as having oligometastatic breast cancer. The number and size of metastases were confirmed using whole-body CT (computed tomography), FDG-PET/CT (positron emission tomography/CT), or MRI (magnetic resonance imaging). All oligometastatic lesions identified on radiological imaging were discussed and reviewed by an institutional radiologist. The ER/PR status and human epidermal growth factor receptor 2 (HER2/neu) status were determined by immunohistochemistry (IHC). In cases where HER2-positive results were equivocal on IHC, fluorescence in situ hybridization (FISH) was performed. HER2 positivity was defined as IHC 3+ or IHC 2+ with positive amplification on FISH. Traditional immunohistochemical biomarkers (ER, PR, HER2, and Ki-67 expression) were used to classify tumors into molecular subtypes. Luminal B (HER2-positive) subtype was defined as ER-positive with PR either positive or negative, and HER2-positive. The HER2-positive/HR-negative tumor subtype was defined as ER-negative, PR-negative, with HER2 amplification or overexpression. Gene expression profiling was not performed due to its unavailability at our center.

Exclusion criteria included patients who had previously received chemotherapy, those treated with palliative intent, patients with relapsed or previously treated HER2-positive breast cancer, and patients with cardiovascular, liver, or pulmonary disease who were unfit for trastuzumab and chemotherapy. All patients underwent pre-NACT evaluation, including a complete medical history, physical examination, baseline blood tests, and imaging studies such as bone scintigraphy, CT scans, MRI, or PET-CT, as per institutional practice. Monitoring was conducted through clinical examination at every visit and imaging after completion of chemotherapy or when clinically indicated. Radiological response to treatment in solid tumors was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Out of 1,200 patients diagnosed with breast carcinoma during the study period, only 100 patients with HER2-positive locally advanced breast cancer received the neoadjuvant FinHer protocol. A baseline cardiac clinical examination and echocardiography were performed as part of routine pre-chemotherapy evaluation. Echocardiographic assessments were conducted at baseline before initiating weekly trastuzumab and again before starting FEC therapy. Only patients with adequate cardiac function, defined as a normal LVEF ≥50% on echocardiography, were included. Patients with a documented history of congestive heart failure, myocardial infarction, angina requiring medication, uncontrolled hypertension, clinically significant valvular disease, or unstable arrhythmias were excluded. However, patients with controlled hypertension on medication and diabetes were included. Cardiotoxicity was defined as a decrease in LVEF below 50%, an absolute reduction of more than 10 percentage points from baseline, or the presence of signs or symptoms of heart failure.

Those patients with an asymptomatic drop in EF were serially monitored after withholding trastuzumab and were started on angiotensin receptor blockers (ARBs). Once their EF returned to baseline values, they were rechallenged. Patients with symptomatic cardiac toxicity were not rechallenged. All patients were advised to continue ARB therapy for 6 months after completion of treatment. These patients were monitored for EF loss by echocardiography every month for the first 3 months, every 3 months for the next 6 months, and every 6 months thereafter.

Treatment protocol

Patients received nine weekly intravenous infusions of trastuzumab in combination with docetaxel. Trastuzumab was administered at a dose of 4 mg/kg on day 1 over 90 min, followed by 2 mg/kg weekly thereafter, administered over 30 min. Trastuzumab was given prior to docetaxel, with the first infusion administered on day 1 of the first docetaxel cycle. Docetaxel was administered intravenously every 21 days for a total of three cycles. This was followed by three cycles of 5-fluorouracil (500 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (500 mg/m²) (FEC), administered every 21 days. Additional supportive care was provided as required. Surgery was performed 3 to 4 weeks after completion of neoadjuvant therapy.

As per institutional practice, all patients with stage III disease and oligometastatic disease who were intended for radical treatment after NACT underwent either modified radical mastectomy (MRM) or breast-conserving surgery (BCS). A standardized institutional pathological assessment was performed. Radiation and hormonal therapy were administered according to standard guidelines after completion of the treatment protocol. Patients who were estrogen receptor-positive or progesterone receptor–positive received adjuvant endocrine therapy, such as aromatase inhibitors or tamoxifen, based on menopausal status. All patients who received neoadjuvant therapy were given adjuvant postmastectomy radiation. Post-treatment follow-up was conducted as per institutional practice. Regular follow-up visits were scheduled every 3 months during the first 3 years following treatment, every 6 months from years 4 to 5, and annually thereafter. A physical examination and ultrasound of the abdomen and pelvis were performed every 3 months. CT of the chest, abdomen, and pelvis was performed every 6 months, and a mammogram was performed annually.

Endpoints and definitions

The primary endpoint of the study was the pathological complete response (pCR) rate. The secondary endpoint was OS. pCR was defined as the absence of residual invasive disease in the breast and axilla (ypT0/is, ypN0). This definition allows for the presence of ductal carcinoma in situ (DCIS) in the breast but requires no invasive cancer in the breast and no cancer in the lymph nodes.

OS was calculated from the date of completion of treatment to death from any cause.

The date of the last routine follow-up was used for survival analysis. Patients who missed their scheduled follow-up were contacted telephonically to assess their current status.

Statistical methods

Descriptive statistics were presented as frequencies and percentages for categorical variables, and as mean or median with standard deviation for continuous variables. The statistical significance of categorical variables was assessed using the chi-square test. Progression-free survival was estimated using the Kaplan–Meier method. Survival curves generated using the Kaplan–Meier method were compared using the log-rank test. A p-value < 0.05 was considered statistically significant.

In addition to univariable analyses, a multivariable Cox proportional hazards model was constructed to evaluate factors associated with OS and DFS. Clinically relevant variables, including stage group (stage III vs. oligometastatic), pCR, and hormone receptor status (ER/PR positive vs. negative), were included in the model. However, hormone receptor status could not be reliably estimated in the multivariable model due to limited variability within the dataset. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. Proportional hazards assumptions were assessed using Schoenfeld residuals.

ResultsBaseline characteristics

Table 1 describes the baseline characteristics of patients enrolled in this study population. A total of 100 patients were included in the study. The median age at presentation was 53 years. The major comorbidities were hypertension (24%), diabetes mellitus (33%), and cardiovascular disease (3%). The majority of patients were postmenopausal (68%), followed by premenopausal (23%) and perimenopausal (9%). The stage at presentation was stage III in 76% of patients and oligometastatic disease in 24%. Approximately 66% of patients had luminal B HER2-positive breast cancer, while 34% had HER2-enriched breast cancer. Tumor grade was grade I in 2%, grade II in 32%, and grade III in 66% of patients. Eighty-eight percent of patients underwent MRM, while 12% underwent BCS. All patients received adjuvant radiotherapy. All patients with oligometastatic disease (24%) underwent MRM, and none underwent BCS. Ninety-two percent of patients received 40 Gy in 15 fractions, whereas 8% received 50 Gy in 25 fractions. Sixty-six patients received adjuvant hormonal therapy; among them, 14 received tamoxifen and 52 received aromatase inhibitors. Eighteen patients received zoledronic acid infusions for bone metastasis. The treatment-related toxicities observed in our study are summarized in Table 1. The most common toxicity was hematological, followed by hepatotoxicity, mucositis, pulmonary toxicity, diarrhea, and cardiac toxicity. Among all toxicity grades, 38% of patients experienced grade I toxicity, while 14% experienced grade II toxicity. Five percent of patients developed grade III toxicity. None of the patients experienced grade IV toxicity. Among those with grade III toxicity, three patients had grade III mucositis, and two patients developed grade III pneumonitis secondary to docetaxel. Dose reduction was implemented for the FEC regimen due to grade III mucositis. Docetaxel was discontinued in patients who developed grade III pneumonitis. Pneumonitis was managed with steroids and supportive care. In the overall study population, 66 patients had luminal B HER2-positive disease and received adjuvant hormonal treatment. Seventeen patients (17%) experienced cardiac toxicity in the form of asymptomatic LVEF decline. Only two patients developed symptomatic LVEF decline. In all cases, LVEF returned to baseline after discontinuation of trastuzumab for 2 weeks. All patients were started on ACE inhibitors upon diagnosis of asymptomatic LVEF decline. None of the patients experienced cardiac events.

Study cohortN = 100Median age, years (range)53 (32–73)Comorbidities, n (%)Hypertension24Diabetes mellitus33Coronary artery disease3Menopausal status, n (%)Premenopausal23Postmenopausal68Perimenopausal9Stage, n (%)Stage III76Oligometastatic disease24Grade, n (%)I0II34III66Molecular type, n (%)Luminal B HER2-positive66HER2-enriched34Toxicities, n (%)Hematological toxicities48Cardiotoxicity17Asymptomatic LVEF lossHepatotoxicity6Mucositis5Diarrhea3Pulmonary toxicity4Highest grade of toxicity, n (%)Grade I38Grade II14Grade III5Surgery, n (%)Modified radical mastectomy
(MRM)88Breast conservation surgery
(BCS)12Complete pathological response (pCR), n (%)pCR30No pCR70Radiation, n (%)Adjuvant radiotherapy10040 Gy/15#9250 Gy/25#8Relapse, n (%)42Site of relapse, n (%)Local12Opposite breast1Liver5Bone8Lung7Brain8Survival5-year DFS57.8% ± 5.1%5-year OS61.6% ± 5%

Baseline characteristics.

Bold values indicate statistically significant p-values.

Pathological complete response

pCR was achieved in 30 patients (30%) following the neoadjuvant FinHer protocol, while 70% of patients did not achieve pCR. Breast-only pCR was observed in 38% of patients, axilla-only pCR in 55%, and combined breast and axilla pCR in 30% of patients. Positivity was associated with decreased pCR rates, which was statistically significant (p = 0.002). Patients with the HER2-enriched subtype (47%) achieved higher pCR rates compared to those with the luminal B HER2-positive subtype (21.2%), with a statistically significant p-value of 0.008 (Table 2). None of the variables, including age, menopausal status, or tumor grade, showed a significant association with pCR in patients treated with the FinHer protocol. None of the patients who did not achieve pCR received adjuvant treatment such as T-DM1 due to financial constraints. The most common sites of oligometastasis were bone (18%), lung nodules (4%), and liver (2%). Similarly, the most common sites of metastasis were bone (18%), lung nodules (4%), and liver (2%).

VariablesPCRNo PCRp-value (chi-square)Age <65 years25630.347Age >65 years57Premenopausal and perimenopausal8240.454Postmenopausal2246Stage III24520.540Stage IV (oligometastatic)618Luminal B HER2-14520.008positive1618HER2-enrichedGrade II12220.407Grade III1848

Association of PCR with clinico-pathological variables.

Bold values indicate statistically significant p-values.

Recurrence

At a median follow-up of 46 months (range, 31–60 months), 42 patients (42%) developed recurrence. The site of recurrence was the local chest wall in 12% of patients and the contralateral breast in 1%. Systemic recurrence was observed in 28% of patients, including the brain (8%), bone (8%), lung (7%), and liver (5%). Recurrences were treated with systemic chemotherapy plus trastuzumab in 12% of patients and with a combination of radiotherapy/surgery and chemotherapy plus trastuzumab in 29% of patients. Among the 100 patients, 37 (37%) had died by the last follow-up in April 2023. No patients were lost to follow-up.

Survival of stage III patients

A total of 76 patients with stage III disease were included in this study, excluding 24 patients with oligometastatic disease.

The Kaplan–Meier curve comparing DFS between patients with stage III disease and those with oligometastatic disease is presented in Figure 1. The analysis showed significantly better DFS in stage III patients compared to the oligometastatic group. The 5-year DFS was approximately 67% in stage III patients versus 36% in the oligometastatic group (p = 0.0019) (Figure 1).

Disease-free survival in patients with stage III and oligometastatic disease. Kaplan–Meier curve comparing disease-free survival (DFS) between patients with stage III disease and those with oligometastatic disease. Disease-free survival was significantly better in stage III patients than in the oligometastatic group. The 5-year DFS was approximately 67% in stage III patients versus 36% in the oligometastatic group (p = 0.0019).

A Kaplan–Meier curve demonstrating the comparison of OS between patients with stage III disease and those with oligometastatic disease is shown in Figure 2. It demonstrates significantly better OS in stage III patients compared to the oligometastatic group. The 5-year OS was approximately 60% in stage III patients versus 26% in the oligometastatic group (p = 0.0011) (Figure 2).

Overall survival in patients with stage III and oligometastatic disease. Kaplan–Meier curve comparing overall survival (OS) between patients with stage III disease and those with oligometastatic disease. OS was significantly better in stage III patients than in the oligometastatic group. The 5-year OS was approximately 60% in stage III patients versus 26% in the oligometastatic group (p = 0.0011).

A Kaplan–Meier curve showing DFS among stage III patients stratified by pCR versus no pCR is shown in Figure 3. Patients who achieved pCR demonstrated numerically better DFS compared to those without pCR; however, the difference did not reach statistical significance (log-rank p = 0.091). At baseline, the numbers at risk were 52 in the no-pCR group and 24 in the pCR group. At approximately 50 months, the numbers at risk were 8 and 6, respectively. The estimated DFS at approximately 5 years was visually higher in the pCR group (approximately 83%–84%) than in the no-pCR group (approximately 62%).

DFS in stage III patients with pCR versus no pCR. Kaplan–Meier curve showing disease-free survival (DFS) among stage III patients stratified by pCR status. Patients who achieved pCR demonstrated numerically better DFS than those without pCR; however, the difference did not reach statistical significance (log-rank p = 0.091). At baseline, the numbers at risk were 52 in the no-pCR group and 24 in the pCR group. At approximately 50 months, the numbers at risk were 8 and 6, respectively. The estimated 5-year DFS was higher in the pCR group (approximately 83%–84%) than in the no-pCR group (approximately 62%).

The Kaplan–Meier curve showing OS among stage III patients stratified by pCR versus no pCR is presented in Figure 4. Patients who achieved pCR demonstrated numerically better OS than those without pCR; however, this difference was not statistically significant (log-rank p = 0.20). At baseline, the numbers at risk were 51 in the no-pCR group and 23 in the pCR group. At approximately 50 months, the numbers at risk were 11 and 6, respectively. The estimated 5-year OS appeared higher in the pCR group (approximately 84%) compared with the no-pCR group (approximately 47%).

OS in stage III patients with pCR versus no pCR. Kaplan–Meier curve showing overall survival (OS) among stage III patients stratified by pCR status. Patients who achieved pCR demonstrated numerically better OS than those without pCR; however, the difference was not statistically significant (log-rank p = 0.20). At baseline, the numbers at risk were 51 in the no-pCR group and 23 in the pCR group. At approximately 50 months, the numbers at risk were 11 and 6, respectively. The estimated 5-year OS was higher in the pCR group (approximately 84%) compared with the no-pCR group (approximately 47%).

Among stage III patients, 24 achieved pCR, whereas 52 did not. Of the 52 patients without pCR, 19 experienced recurrence, compared with 4 recurrences among the 24 patients who achieved pCR. The median DFS was 43 months, with a median follow-up of 54 months. There was no statistically significant association between pCR and disease recurrence in stage III patients (p = 0.091) (Supplementary Figure 1). The median OS for stage III patients was 49 months, with a median follow-up of 54 months. Among the 76 patients, there were 4 deaths in the pCR group and 16 deaths in the no-pCR group. There was no statistically significant association between pCR and mortality (p = 0.197) (Supplementary Figure 2).

Among the 76 stage III patients, 25 were ER/PR-negative, of whom 13 achieved pCR. In contrast, among the 51 ER/PR-positive patients, only 11 achieved pCR. There was a statistically significant association between ER/PR negativity and achievement of pCR (p = 0.007).

Survival of oligometastatic disease

Twenty-four patients included in the study had oligometastatic disease at presentation but were treated with radical intent. These patients had a median DFS of 16 months and a median OS of 32 months. Among the 24 patients with oligometastatic disease, 6 achieved pCR, while 18 did not. Approximately 15 patients with luminal B HER2-positive disease in the oligometastatic group received adjuvant hormonal therapy. All patients with oligometastatic disease who underwent NACT experienced relapse by the last data cutoff.

Cox regression analysis

On univariate analysis, stage was the only significant predictor of DFS (p = 0.003) and OS (p = 0.002) (Table 3). None of the other factors—age, menopausal status, tumor grade, pathologic complete response (pCR vs. no pCR), type of surgery (BCS vs. MRM), or molecular subtype (luminal B HER2-positive vs. HER2-enriched)—were significantly associated with DFS or OS.

VariablesOS univariate analysisDFS univariate analysisHazard ratioConfidence intervalp-valueHazard ratioConfidence intervalp-valueAge <65 years10.73710.219Age >65 years0.8410.298–2.3740.4790.148–1.549Premenopausal and perimenopausal10.24210.0820.6680.34–1.290.5800.314–Postmenopausal1.071Stage III11Stage IV oligometastatic2.9161.5–5.650.0022.6231.38–4.90.003Luminal B HER-210.92410.815positive1.0330.526–2.031.0790.568–HER2-enriched2.051Grade II10.38210.110Grade III1.340.69–2.591.640.89–3.03PCR10.14310.109No PCR1.7460.79–3.821.830.874–3.84BCS10.73710.39MRM2.910.7–12.11.50.5–4.31

Univariate analysis of OS and DFS.

Bold values indicate statistically significant p-values.

Multivariable Cox regression analysis, including stage group, pathologic complete response (pCR), and hormone receptor status, was performed for OS and DFS (Table 4). Stage III disease remained independently associated with improved survival outcomes compared with oligometastatic disease (OS: HR 0.35, 95% CI 0.18–0.70, p = 0.003; DFS: HR 0.40, 95% CI 0.21–0.76, p = 0.005). Achievement of pCR was associated with a numerically lower risk of death and recurrence (OS: HR 0.56, 95% CI 0.24–1.30; DFS: HR 0.51, 95% CI 0.22–1.16), although these differences did not reach statistical significance. Hormone receptor status was included in the multivariable model; however, its effect could not be estimated reliably, as the model yielded a non-estimable coef