Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer
Original Article

Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer

Lu Yao1*, Juan Zhang1*, Yiqiang Liu2, Tao Ouyang1, Jinfeng Li1, Tianfeng Wang1, Zhaoqing Fan1, Tie Fan1, Benyao Lin1, Yuntao Xie1

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), 1Breast Center, 2Department of Pathology, Beijing Cancer Hospital & Institute, Peking University Cancer Hospital, Beijing 100142, China

*These authors contributed equally to this work.

Correspondence to: Yuntao Xie, MD, PhD. Breast Center, Beijing Cancer Hospital & Institute, Peking University Cancer Hospital, Beijing 100142, China. Email: zlxyt2@bjmu.edu.cn.

Background: We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab.

Methods: Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy.

Results: Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002).

Conclusions: Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.

Keywords: HER2; breast cancer; neoadjuvant chemotherapy; paclitaxel; carboplatin

Submitted Sep 10, 2015. Accepted for publication Dec 04, 2015.

doi: 10.3978/j.issn.1000-9604.2015.12.03

Introduction

Pathologic complete response (pCR) after neoadjuvant chemotherapy is associated with favorable clinical outcome (1-8) and it serves as a surrogate marker of treatment efficacy.

Anthracyclines and taxanes (paclitaxel or docetaxel) are the most effective cytotoxic agents in breast cancer and form the backbone of most regimens used in the neoadjuvant settings (2,8-10). Several randomized clinical trials demonstrated that the sequential use of paclitaxel after doxorubicin and cyclophosphamide (AC) significantly improved survival as compared with AC alone in both neoadjuvant and adjuvant settings (11-13).

HER2, a member of the epidermal growth factor receptor family, is overexpressed in approximately 20% to 25% of breast cancers and is associated with an unfavorable clinical outcome (14,15). Currently, adjuvant chemotherapy in combination with trastuzumab is a standard therapy for HER2-positive operable primary breast cancers (16,17). We previously showed that HER2-positive breast cancers are less likely to respond to anthracycline-based neoadjuvant chemotherapy in the absence of trastuzumab (18). In contrast, two studies indicated that HER2-positive tumors are likely to benefit from paclitaxel in both adjuvant and metastatic settings under the situation of no trastuzumab treatment (12,19). To date, few studies are available for investigating the association between HER2 status and pathologic response in patients who received neoadjuvant paclitaxel-based regimen (20-23).

Although trastuzumab dramatically improves the survival for HER-2 positive breast cancers (16,24), however, at least one third of Chinese women with HER2-positive breast cancer cannot receive such treatment due to expensive of this targeted therapy. And the disease burden of breast cancer is increasing annually in China (25-27). Therefore, in the current study, we investigated association between the HER2 status and pathologic response in 372 patients who received sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen without trastuzumab.

Materials and methods

Study population

From April 2003 to November 2008, three hundred seventy-two operable breast cancer patients with stage I to III disease (T1-3, N0-2, M0) were received two cycles anthracyclines followed by 4 cycles paclitaxel plus carboplatin neoadjuvant chemotherapy at the Breast Center, Peking University Cancer Hospital. Patients with HER2-positive tumors in this cohort of 372 patients did not receive neoadjuvant trastuzumab treatment. All patients gave written consent. This study was approved by the Research and Ethics Committee of Peking University Cancer Hospital.

Treatment and response

Three hundred seventy-two patients initially received two cycles of anthracycline-based regimens. Among them, 352 patients received CTF (5-fluorouracil, pirarubicin, and cyclophosphamide) regimen; 16 patients received FEC (5-fluorouracil, epirubicin, and cyclophosphamide) regimen; 4 patients received CAF regimen (5-fluorouracil, doxorubicin, and cyclophosphamide). The detail of the regimens are described previously (18).

After two cycles of anthracyclines, the clinical response of the primary breast cancer was assessed. The clinical size of the primary breast cancer was determined by ultrasound before the start of chemotherapy and after two cycles of anthracyclines, the products of the two greatest perpendicular diameters of primary breast cancer were calculated. Patients in whom the primary breast cancers achieved a partial (reduction of tumor size ≥50%) or complete response after the two cycles were considered as responders; those whose tumors did not achieve a partial response (reduction of tumor size less than 50% or tumor size increase) were considered as non-responders. Both responders and non-responders were received 4 cycles of paclitaxel plus carboplatin regimen. Paclitaxel 175 mg/m2, IV on day 1, carboplatin AUC6, IV on day 1, every 21 day; or paclitaxel 60 mg/m2, IV on day 1, day 8, day 15, carboplatin AUC6, IV on day 1, every 21 day.

After completion of neoadjuvant chemotherapy, patients received either mastectomy or breast conserving therapy (BCT). Pathologic complete response was defined as no invasive breast tumor cells in the breast after completion of neoadjuvant chemotherapy (1,5,7).

Estrogen receptor (ER), progesterone receptor (PgR), and HER2 status

ER, PgR, and HER2 status were determined using the core-needle biopsy breast cancer tissue obtained before initiation of neoadjuvant chemotherapy. ER and PgR were assessed by immunohistochemical assay (18) .

HER2 status was determined by immunohistochemical assay and/or by fluorescence in situ hybridization (FISH) in core-biopsy breast cancer tissue (18).

Statistics analysis

The associations between HER2, clinicopathologic characteristics, and pathologic response to neoadjuvant chemotherapy were determined using Pearson’s χ2 test. A logistic regression model was applied to determine whether a factor was independent predictor of pCR in a multivariate analysis. All statistical tests were two-sided, and P values less than 0.05 were considered as significant. The statistical analyses were performed using SPSS 16.0 software (Chicago, IL, USA).

Results

Associations between HER2 and clinicopathologic characteristics and pCR

The baseline characteristics of the 372 patients are presented in Table 1. Eighteen percent of patients achieved pCR in this cohort of 372 patients (Table 1). Age, tumor size, surgery, and triple-negative breast cancer (ER-, PgR-, and HER2-) were not significantly associated with the pathologic response (Table 1). Patients with lymph-node positive tumors were less likely to achieve a pCR compared with patients with lymph-node negative tumors (9.2% versus 25.0%, P<0.001) (Table 1). ER- or PgR-negative tumors had a higher pCR rate than ER- or PgR-positive tumors (ER, 29.7% versus 12.9%, P<0.001; PgR, 25.0% versus 13.3%, P=0.004), high-grade tumors also had a higher pCR rate than low-grade tumors (III versus I+II: 45.1% versus 14.4%, P<0.001) (Table 1).

HER2 results were available for 366 patients, with 24.9% of patients having a HER2-positive tumor (Table 1). Patients with HER2-positive tumors had a significantly higher pCR rate than did patients with HER2-negative tumors in this cohort (33.0% versus 13.5%, P<0.001) (Table 1). If the pCR was defined as no invasive breast tumor cells in both breast tumors and axillary lymph nodes, there was also a significant association between HER2 status and pCR, HER2-positive tumors showed a higher pCR rate than did HER2-negative tumors in this analysis (27.5% versus 9.8%, P<0.001) (data not shown).

Multivariate analysis revealed that HER2 was an independent favorable predictor of pCR after adjusted for age (≤50 versus >50 yr), tumor size (≤2 versus >2 cm), ER (negative versus positive), PgR (negative versus positive), and tumor grade (III versus I+II) in this cohort of 372 patients [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015] (Table 2). Patients with HER2-positive tumors were 2.3-fold more likely to respond to neoadjuvant anthracyclines followed by paclitaxel plus carboplatin regimen than patients with HER2-negative tumors. Furthermore, high tumor grade remained as an independent favorable predictor of pCR (Table 2).

Table 1
Table 1 Association of HER2 and tumor characteristics with pathologic response
Full table
Table 2
Table 2 Multivariate logistic regression model for pathologic complete response
Full table

Association between HER2 and pathologic response in anthracycline response and non-response subgroups

Among the 372 patients, the clinical response was assessed after the two initial cycles of anthracyclines in 363 patients (Table 1). Of these, one hundred and three patients (28.4%) reached a partial or complete response (anthracycline response group), while the remaining 260 patients (71.6%) had stable or progressive disease (anthracycline non-response group) (Table 1). After further treatment with four cycles of paclitaxel plus carboplatin, patients in the anthracycline response group were more likely to respond to paclitaxel plus carboplatin than patients in the anthracycline non-response group (pCR rate: 27.2% versus 14.6%, P=0.005) (Table 1).

HER2-positive tumors had a significant higher pCR rate than did HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) (Table 3) and anthracycline non-response group (28.3% versus 11.3%, P=0.002) (Table 4). Triple-negative tumors tended to have a higher pCR rate than did non-triple-negative tumor in anthracycline response group (38.5% versus 26.1%, P=0.342) (Table 3); but this was not the case in the anthracycline non-response group (12.2% versus 15.3%, P=0.603) (Table 4).

Table 3
Table 3 Association of HER2 and tumor characteristics with pathologic response in 103 patients who respond to two initial cycles of anthracycline
Full table
Table 4
Table 4 Association of HER2 and tumor characteristics with pathologic response in 260 Patients who did not respond to two initial cycles of anthracycline
Full table

Discussion

We showed that patients with HER2-positive tumors are more likely to benefit from sequential anthracyclines followed by paclitaxel plus carboplatin chemotherapy than those with HER2-negative tumors in a neoadjuvant setting; and HER2 remained as an independent favorable predictor of pCR to this neoadjuvant chemotherapy in a multivariate analysis.

Although most previous studies indicated that patients with HER2-positive tumors are more likely to benefit from adjuvant anthracycline-based chemotherapy (28,29); Bartlett et al. (30) showed that patients with HER2-negative tumor gain a larger benefit from epirubicin than do patients with HER2-positive tumors in an adjuvant setting. We recently also found that HER2-negative tumors have a higher pCR rate than HER2-positive tumors (25.7% versus 14.7%, P=0.013) in 538 operable primary breast cancer patients who received neoadjuvant anthracycline-based chemotherapy (18). Therefore, our previous study together with Bartlett study suggested that HER2-positive tumors are less likely to benefit from anthracycline chemotherapy in both adjuvant and neoadjuvant settings.

In the present study, the observation that HER2-positive tumors had a higher pCR rate than HER2-negative tumors is therefore likely due to the effect from paclitaxel or combined with carboplatin. Our finding was concordant with previous observation that paclitaxel is more efficacious in HER2-positive tumors than in HER2-negative tumors in both adjuvant and metastatic settings (12,19). Hayes et al. (12) showed that patients with HER2-positive tumors benefit from the addition of paclitaxel after receiving four cycles of doxorubicin plus cyclophosphamide in an adjuvant setting.

In this study, patients who responded to two initial cycles of anthracycline were more likely to respond paclitaxel plus carboplatin than those who did not. This finding is agreement with a previous study that patients who respond to initial chemotherapy regimen are more likely to respond to additional non-cross-resistant therapy (8). On the other hand, patients who do not respond to initial neoadjuvant chemotherapy are unlikely to respond to a non-cross-resistant regimen in both Aberdeen trial (8) and GeparTrio trial (31). In the Aberdeen trial (8), patients who do not respond to four initial cycles of anthracycline are unlikely to respond to docetaxel, the pCR rate is only 2% in non-response group in this trial. In our present study, the pCR rate was 14.6% in the anthracycline non-response group and it is higher than that of Aberdeen trial. The discrepancy between our study and Aberdeen study may be due to two reasons. First, our regimen contains paclitaxel plus carboplatin compared with single agent docetaxel in Aberdeen study; second, 38.1% of patients with small tumor size (i.e., ≤2 cm) were in our cohort compared with only large and advanced breast cancers in Aberdeen study. Small tumors are more likely to achieve pCR in many studies. Due to no anthracycline alone arm in our study, we cannot rule out that patients who do not respond to anthracycline may gain additional benefit from paclitaxel plus carboplatin regimen. Nevertheless, after completion of four cycles of paclitaxel plus carboplatin, patients with HER2-positive tumors had a significantly higher pCR rate than HER2-negative tumors in both anthracycline response group and anthracycline non-response group. These findings suggested that HER2-positive tumors derive a larger benefit from paclitaxel-carboplatin-based regimen in anthracycline response and non-response groups.

In the present study, triple-negative tumors did not have a higher pCR rate than non-triple-negative tumors in the entire cohort of 372 patients. It has been postulated that triple-negative tumors are sensitive to DNA-damaging chemotherapeutic agents like the platinum analogs (32). A recent study showed that only 22% of patients achieved pCR in 28 triple-negative patients who received neoadjuvant single cisplatin agent (33). Although carboplatin is a component in our present regimen, we failed to find triple-negative tumors significantly responded to paclitaxel plus carboplatin regimen. However, in the anthracycline response group, triple-negative breast cancers tended to have a higher pCR rate than non-triple negative breast cancers, but such tendency was not found in the anthracycline non-response group. We previously found triple-negative breast cancers are more likely to respond to neoadjuvant anthracycline (18).

In conclusion, our study indicated that patients with HER2-positive tumors are more likely to respond to paclitaxel-carboplatin-based regimen in a neoadjuvant setting no matter whether the tumors respond to initial anthracycline or not. Since some HER2-positive breast cancer patients do not have a chance to receive trastuzumab treatment due to economic issues in China, these patients can gain a large benefit from anthracycline followed by paclitaxel plus carboplatin neoadjuvant chemotherapy without trastuzumab treatment.

Acknowledgements

Funding: This study was supported by grants from the National Natural Science Foundation of China (No.81302330, No. 30973436 and No. 81071629); the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No. 2014BAI09B08); the 973 project 2013CB911004 and the 985-III project.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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Cite this article as: Yao L, Zhang J, Liu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y. Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer. Chin J Cancer Res 2015;27(6):553-561. doi: 10.3978/j.issn.1000-9604.2015.12.03