The aim of this study was to evaluate the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or nonanthracycline-based regimen.
In this retrospective nonrandomized study, the authors reviewed records of 300 patients with HER2-positive breast cancer treated with either sequential paclitaxel and trastuzumab and FEC75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin, and trastuzumab (TCH). The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models and Cox proportional hazards models were fit to determine the associations between NST, pCR, and survival.
There was no significant difference in the decline in cardiac ejection fraction; however, patients who received PH-FECH had fewer cardiac comorbidities at baseline (P = .002). pCR rates were 60.6% and 43.3% for patients who received PH-FECH (n = 235) and TCH (n = 65), respectively (P = .016). Patients who received PH-FECH were 1.45 times more likely to have a pCR (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-1.98; P = .02). Three-year RFS rates were 93% and 71% (P < .001), and 3-year OS rates were 96% and 86% (P = .008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (hazard ratio [HR], 0.27; 95% CI, 0.12-0.60; P = .001) and death (HR, 0.37; 95% CI, 0.12-1.13; P = .08) than those treated with TCH.
Neoadjuvant systemic therapy (NST) has been the standard of care for patients with inflammatory and locally advanced breast cancer and is increasingly being used for early-stage disease. NST allows the measurement of treatment response in addition to survival. Several studies have indicated that pathologic complete response (pCR) to NST is predictive of improved recurrence-free survival (RFS) and overall survival (OS).1-3
With the introduction of anthracycline-based regimens, 5-year survival rates have significantly improved in patients with early-stage breast cancer.4 With the addition of trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), improvements in OS have been observed among patients with advanced HER2-positive disease.5, 6 However, in a pivotal phase III trial in metastatic breast cancer, the concurrent administration of anthracyclines and trastuzumab resulted in an unacceptably high rate (27%) of cardiotoxicity.7 Findings from the N9831 adjuvant trial suggested the superiority of concomitant chemotherapy and trastuzumab (doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab) over sequential use of the same therapies (doxorubicin plus cyclophosphamide followed by paclitaxel, followed by trastuzumab).7-9 Although cardiotoxicity was more frequent with sequential doxorubicin/cyclophosphamide and taxane-trastuzumab than nonanthracycline-based trastuzumab regimens, the majority of patients who received therapy displayed neither acute nor delayed cardiac dysfunction (CD). Afterward, several studies10-12 have evaluated concurrent administration of anthracycline-based chemotherapy and trastuzumab in the neoadjuvant setting. In contrast to previous reports, trastuzumab plus anthracycline-based NST was both effective and well tolerated.
Therefore, we conducted this retrospective analysis to determine the efficacy of concurrent trastuzumab in combination with anthracycline-based or nonanthracycline-based NST. Our primary objective was to compare the pCR rates between the 2 treatment groups. Secondary end points included clinical and radiologic response rates, RFS, and OS.
MATERIALS AND METHODS
The Breast Cancer Management System database of The University of Texas MD Anderson Cancer Center (MDACC) identified 300 women who were diagnosed with HER2-positive invasive breast cancer and treated with NST using either sequential paclitaxel and trastuzumab and FEC-75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin, and trastuzumab (TCH) between 2001 and 2009. We excluded patients who were male, who had metastatic disease, bilateral breast cancer, or more than 1 primary tumor, whose pathologic response could not be assessed, or who were enrolled in the American College of Surgeons Oncology Group (ACOSOG) Z1041 trial. Initial clinical and final pathologic stage were based on the seventh edition of the American Joint Committee on Cancer (AJCC) staging criteria.13
The study was approved by the MDACC Institutional Review Board. Accuracy of clinical variables recorded within the database was verified by retrospective review of patient records.
Pathologic specimens were reviewed by dedicated breast pathologists at MDACC. Histologic type and grade were defined according to the World Health Organization (WHO) classification system14 and modified Black's nuclear grading system,15 respectively. Nuclear staining ≥10% of estrogen-receptor (ER) or progesterone-receptor (PR) was considered strongly positive. HER2 positivity was defined as 3+ receptor overexpression on immunohistochemistry (IHC) staining and/or gene amplification on fluorescence in situ hybridization (FISH).
The type of NST was at the discretion of the patient and treating oncologist; 235 patients received PH-FECH, and 65 received TCH chemotherapy. PH-FECH included paclitaxel 80 mg/m2 intravenously (IV) weekly for 12 weeks or paclitaxel 225 mg/m2 IV over 24 hours every 3 weeks, followed by 4 cycles of FEC-75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2) IV on day 1, every 3 weeks. A loading dose of 4 mg/kg IV trastuzumab was given on day 1 followed by 2 mg/kg weekly, during the 24 weeks of NST. The nonanthracycline-based NST (TCH) included docetaxel 75 mg/m2 IV on day 1, carboplatin at an area-under-the-concentration curve (AUC) of 6 IV on day 1, and trastuzumab 8 mg/kg IV on day 1 followed by 6 mg/kg maintenance dose, administered at 3-week intervals for 6 cycles. PH-FECH and TCH NST were given as planned in 231 (98%) and 61 patients (94%), respectively. However, 7 patients who received PH-FECH (2%) and 9 that received TCH (14%) did not complete a year of trastuzumab.
Surgical intervention was breast-conserving surgery (BCS) for 29% of patients (n = 87) and mastectomy for 68% (n = 204); 3% (n = 9) did not have surgery as a result of the development of progressive disease or patient refusal. Radiation therapy was given for patients who had BCS, locally advanced disease, or inflammatory breast cancer (IBC). Women with hormone receptor-positive disease were offered 5 years of adjuvant endocrine therapy.
Response and Toxicity Assessments
A clinical complete response (cCR) was defined as no detectable disease in breast and axilla on physical examination. Radiologic response was evaluated at baseline and before surgery based on Response Evaluation Criteria in Solid Tumors [RECIST].16 pCR was defined as the absence of invasive disease in the breast and the absence of micro- or macrometastases in the ipsilateral axillary lymph nodes. Left ventricular ejection fraction (LVEF) was evaluated by an echocardiogram (ECHO) or multigated cardiac blood pool scan (MUGA) at baseline, 3, 6, 12, and 18 months after initiation of NST. Adverse events (AEs) for nonlaboratory toxicities were summarized according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.17
Statistical Analysis and Outcome Measures
Patient demographics, clinical characteristics, pCR rate, comorbidities, and AEs were compared between the 2 groups with chi-square test. Multivariate logistic regression models were fitted to examine the relation between NST groups and pCR. RFS was defined as the time from the first dose of NST until the first date of documented local or distant recurrence or the date of last follow-up. Patients who died from unrelated causes were censored. OS was measured from the first dose of NST until the date of death from any cause or last follow-up. Survival outcomes were estimated with the Kaplan-Meier product-limit method. Cox proportional hazards models were fitted to determine the association of NST with survival outcomes after adjustment for significant patient and clinical characteristics identified in univariate analyses. Statistical analyses were carried out using SAS 9.1 (SAS Institute Inc., Cary, NC) and S-Plus 7.0 (Insightful Corporation, Seattle, WA).
Three hundred patients were included in the study; 235 (78%) were treated with PH-FECH, and 65 (22%) with TCH. Patient demographics and clinical characteristics are summarized in Table 1. Patients treated with PH-FECH were younger (P = .005), had lower tumor stage (P = .001), and were less likely to have IBC (P < .001) compared with patients treated with TCH. Patients who received PH-FECH at baseline had fewer cardiac comorbidities (P = .002) and cardiac risk factors (P = .12) when compared with patients who received TCH (Table 1).
Table 1. Patient Demographics and Baseline Clinical Characteristics by Neoadjuvant Systemic Chemotherapy Type
Of 300 patients, 80.8% had cCR in the PH-FECH group versus 58.9% in the TCH group (P = .006; Table 2). The radiologic overall response rates (ORR) were 97.0% in the PH-FECH group versus 98.1% in the TCH group (P = .67). Excluding IBC patients, cCR rates were 79.9% and 51.3% (P = .002), and radiologic ORR were 97.2% and 97.3% (P = .98) in the PH-FECH and TCH groups, respectively.
Table 2. Pathologic Complete Response and Clinical Response Rates by Neoadjuvant Systemic Chemotherapy Type
The pCR rate was significantly higher in patients treated with PH-FECH compared with patients treated with TCH (60.6% vs 43.3%; P = .016) (Table 2). In the PH-FECH group, pCR was achieved in 57% (105 of 183) of patients treated with weekly paclitaxel and 61% (32 of 52) of patients treated with every 3-week paclitaxel.
pCR rate was higher for ER− compared with ER+ tumors in both the PH-FECH (70.3% vs 47.6%) and the TCH group (57.1% vs 25.7%). The pCR rate with PH-FECH versus TCH, respectively, was 64.1% (93 of 145) versus 39.4% (13 of 33) for T1/2 tumors, 52.3% (22 of 42) versus 50%(3 of 6) for T3 tumors, 35.7% (10 of 28) versus 50% (2 of 4) for T4b tumors, and 55.5% (10 of 18) versus 38.1% (8 of 21) for IBC. Excluding the IBC patients, pCR rate was 60.5% for patients who received PH-FECH compared with 42.9% for those who received TCH (P = .035).
On multivariate analysis, PH-FECH was associated with a higher pCR rate (odds ratios [OR], 1.45; 95% confidence interval [CI], 1.06-1.98; P = .02). In addition, patients with ER-negative/weak tumors (P < .001), higher nuclear grade (P = .05), and pretreatment T1-3 status (P = .043) were more likely to achieve a pCR (Table 3). After excluding the IBC patients, PH-FECH remained an independent significant predictor for pCR (OR, 1.46; 95% CI, 1.02-2.08; P = .039).
Table 3. Multivariate Logistic Regression Model for Pathologic Complete Response
BMI, body mass index; CI, confidence interval; ER, estrogen receptor; OR, odds ratio; pCR, pathologic complete response; PH-FECH, taxol/5-FU/epirubicin/cytoxan/herceptin; TCH, taxotere/carboplatin/herceptin.
PH-FECH vs TCH
Age, y: >50 vs ≤50
Race: black vs non-black
BMI: overweight/obese vs normal/underweight
ER status: positive vs negative/weak
Grade: III vs II
Clinical T: T4 vs T1-3
Clinical N: N1-3 vs N0
Median follow-up of survivors was 26.8 months (range, 5-99 months); the follow-up was 29 months and 18 months for the PH-FECH group and the TCH group, respectively. The estimated 3-year RFS was 93% in the PH-FECH versus 71% in the TCH group; P < .001 (Table 4). Excluding IBC patients, the 3-year RFS estimates were again better for the patients who received PH-FECH compared with the patients who received TCH (94% vs 80%; P = .01) (Fig. 1C).
Table 4. Three-Year Recurrence-Free and Overall Survival Estimates in Patient Subgroups
3-Year Estimates (95% CI)
3-Year Estimates (95% CI)
BMI, body mass index; CI, confidence interval; ER, estrogen receptor; pCR, pathologic complete response; PH-FECH, taxol/5-FU/epirubicin/cytoxan/herceptin; TCH, taxotere/carboplatin/herceptin.
Outcomes of patients who achieved pCR presented by treatment received.
Patients who achieved pCR had better RFS than patients who did not (95% vs 83%; P = .003). Among patients with pCR, patients who received PH-FECH had better 3-year RFS compared with TCH (97% vs 82%; P = .008). In the multivariate model, PH-FECH was associated with a lower risk of recurrence (hazard ratio [HR] = .27; 95% CI, 0.12-0.60; P = .001). This association remained when excluding IBC patients (HR = 0.28; 95% CI, 0.10-0.82; P = .02).
The 3-year OS estimates were 96% in the PH-FECH group compared with 86% in the TCH group (P = .008). Patients who achieved pCR had better 3-year OS than patients who did not (98% vs 93%; P = .008). Among patients with pCR, patients who received PH-FECH had better 3-year OS compared with patients who received TCH (100% vs 76%; P < .001). In the 261 patients without IBC, there were no differences in the 3-year OS estimates for the patients who received PH-FECH compared with the patients who received TCH (96% vs 100%; P = .98). The multivariate Cox proportional hazards model showed that PH-FECH tended to be associated with a lower risk of death (HR = 0.37, 95% CI, 0.12-1.13; P = .08). When excluding patients with IBC, there was no association (HR = 1.06; 95% CI, 0.13-8.61; P = .96).
No significant differences were noted in nonlaboratory AEs and cardiotoxicity with respect to NST regimen received (Table 5). The mean left ventricular ejection fraction (LVEF) at baseline was 64.3% in the PH-FECH group and 64.7% in the TCH group. The mean calculated percent decline in LVEF from baseline to the lowest detected during follow-up was 8% in both treatment groups (P = .52). However, 1 patient on PH-FECH developed congestive heart failure and died from sudden cardiac death.
Table 5. Adverse Events by Neoadjuvant Systemic Chemotherapy Type
PH-FECH, taxol/5-FU/epirubicin/cytoxan/herceptin; SD, standard deviation; TCH, taxotere/carboplatin/herceptin.
2-sample t test.
Calculated as percent ejection fraction drop from baseline to the lowest ejection fraction among 3, 6, 12, and 18 months.
Several trials have examined the potential benefits of concurrent trastuzumab in combination with anthracycline-based11, 12, 18-21 or nonanthracycline-based neoadjuvant therapy22-29 in HER2-positive breast cancer, with reported pCR rates of up to 76%.30 In this retrospective nonrandomized study, we showed that although TCH is active, trastuzumab combined with a taxane and then with an anthracycline (PH-FECH) shows higher pCR rate.
The high pCR rates in our study are consistent with previous trials that assessed the use of trastuzumab as part of an anthracycline-based NST regimen in operable and locally advanced breast cancer. In the MDACC10 trial, patients with HER2-positive breast cancer received paclitaxel followed by FEC75, with or without concurrent trastuzumab. The pCR rate increased from 26% to 65% (P = .02) with trastuzumab. An expansion cohort in the experimental arm (n = 22) continued to show high rates of pCR (54.5%) without significant cardiac toxicity.19 The combined pCR rate for all patients who received trastuzumab was 60%, and at a median follow-up of 36.1 months, there had been no recurrences. The Neoadjuvant Herceptin (NOAH) trial evaluated the sequential administration of 3 cycles of doxorubicin and paclitaxel followed by 4 cycles of paclitaxel alone, then 3 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil with or without concomitant trastuzumab.11 Patients with HER2-positive disease who received concurrent trastuzumab had a significantly higher pCR rate (43% vs 23%; P = .002), ORR (89% vs 77%; P = .02), and 3-year disease-free survival (DFS) (70.1% vs 53.3%; P = .007) compared with those who received chemotherapy alone. A pCR benefit with the addition of trastuzumab was also observed among IBC patients (39% vs 20%; P = .002). In the phase III German Breast Group/Gynecologic Oncology Study Group trial (the GeparQuattro trial),12 patients with HER2-positive locally advanced breast cancer were treated with epirubicin/cyclophosphamide followed by docetaxel with or without capecitabine, and trastuzumab every 3 weeks. Neoadjuvant trastuzumab plus chemotherapy demonstrated a significant increase in pCR rates (15.7% vs 31.7%; P < .001). pCR rates with neoadjuvant trastuzumab and anthracycline-free regimens in other studies range from 11% to 76%.22, 24, 25, 30-35
Due to concerns about cardiotoxicity, there has been interest in developing nonanthracycline-containing regimens. BCIRG 00636 evaluated AC followed by docetaxel (AC/T) versus AC followed by docetaxel plus trastuzumab (AC/TH) versus TCH for the adjuvant treatment of HER2-positive breast cancer. In a recent updated analysis with 656 DFS events, DFS was improved by 36% with AC/TH (P = .001) and by 25% with TCH (P = .04) relative to the AC/T arm. The risk of death was reduced by 37% with AC/TH (P < .001) and 23% with TCH (P = .038) relative to the AC/T arm.37 There was no statistically significant difference in 5-year DFS (P = .21) and OS (P = .14) between the trastuzumab-containing regimens. The results of this trial not only confirmed the importance of trastuzumab for HER2-positive breast cancer, but it also greatly increased interest in the use of nonanthracycline-trastuzumab–based regimen, TCH, for adjuvant therapy.
In our study, PH-FECH and TCH NST yielded different pCR rates (60.6% vs 43.3%; P = .016). However, pCR rates relate inversely to larger tumor size, lower nuclear grade, and ER-positivity.22, 37 In addition to the significant differences in age and T stage between our study groups, the patients in the TCH group were more overweight and had more frequent unfavorable disease characteristics (nonductal histologies, stage IIIB, and N1/2 disease) that may have led to lower pCR rates and worse survival outcomes. In our multivariate analysis, PH-FECH demonstrated superiority in clinical outcome even when other variables were considered. Although the multivariable analysis compensates for much of the covariate imbalances, it probably does not account for all. It remains to be determined whether the differences in outcomes between the groups were the result of the antitumor effect of anthracyclines, synergy from the combination of anthracyclines with trastuzumab, or the additional duration of therapy. Future randomized studies with larger prospective cohorts and longer-term follow-up are needed to validate these findings.
Although trastuzumab-based therapies have been associated with an increased incidence of cardiac dysfunction (CD), especially when combined with anthracyclines, 3 large clinical trials10-12 demonstrated that the combination was both effective and well tolerated. Overall, the CD incidence in the neoadjuvant and adjuvant settings ranged from none observed10, 27 to 10.5%,38 and 2.0%36 to 3.3%,39, 40 respectively. Caution should be exercised in women with risk factors for cardiac toxicity because data from B-31 indicate that women who develop severe cardiac toxicity from anthracycline-based regimens do not always fully recover.41 In addition, B-3141 and N983142 demonstrated that 5.0% to 6.6% of women who received anthracyclines were unable to receive trastuzumab. Nonetheless, in the GeparQuattro trial12 concurrent administration of trastuzumab with epirubicin yielded persistent decrease in LVEF to <50% in only 1 patient. In this study, although the patients who received TCH had more baseline cardiac comorbidities and cardiac risk factors, there were no differences in the baseline LVEF or magnitude of decrease in the LVEF after NST.
The treatment benefits need to be weighed against the risk of cardiotoxicity. The cardiac death in a patient who received PH-FECH further highlights the importance of careful patient selection and close cardiac monitoring. One potential approach to minimize cardiotoxicity would be to administer trastuzumab after completion of anthracyclines. However, the comparative antitumor efficacy of this approach is not known. This specific question is currently being tested in the ongoing ACOSOG Z1041 trial.
Our study is limited by its retrospective nature and small sample size in the TCH cohort. Patient selection for individual treatment regimens may have impacted the differences in oncologic outcome. Fewer patients with cardiac comorbidities received PH-FECH, which may have minimized CD observed in the anthracycline cohort. On the other hand, we showed that the incidence of CD is comparable to previous trials in which more selective eligibility criteria and better cardiac monitoring are applied.
In conclusion, the results of our retrospective analysis suggest that the type of NST in HER2-positive breast cancer is predictive of pCR rate independent of disease characteristics. Although TCH is active, trastuzumab combined with an anthracycline-based NST showed higher pCR rate and a RFS advantage.
This work is supported in part by National Cancer Institute 1K23CA121994-01 to A.M.G. The MD Anderson Breast Cancer Management System is supported in part by the Nelly B. Connally Breast Cancer Research Fund.