Outcome of neoadjuvant chemotherapy in locally advanced breast cancer: A tertiary care centre experience.

BACKGROUND: Introduction of neoadjuvant chemotherapy (NACT) has dramatically changed the management of locally advanced breast cancer (LABC). However, very few randomized trials of NACT have been carried out specifically in LABC patients in our country. In this retrospective analysis, we presented our experience with NACT in LABC patients.
MATERIALS AND METHODS: Medical records of 148 patients of stage III LABC patients treated with NACT, followed by surgery and radiotherapy from January 2006 to December 2010 were reviewed. Clinical and pathological responses to different chemotherapy regimens were assessed according to World Health Organization criteria. Various factors influencing response to NACT and clinical outcome were identified and analyzed.
RESULTS: A total of 90 (60.8%) patients received anthracycline-based chemotherapy and 52 (35.1%) patients received mixed anthracycline and taxane-based chemotherapy.119 patients (80.4%) responded to NACT either in the form of complete or partial response (PR). Complete response was seen in 27 (18.2%) patients and 92 (62.2%) patients showed PR after NACT. Pathological complete response was seen in 24 (16.2%) patients-. At a median follow-up period of 44 months 36 patients (24.3%) developed relapse of which six patients developed locoregional recurrence, while 28 (18.9%) patients developed distant metastasis. Nodal status, response to chemotherapy, pathological tumor size <3 cm and extracapsular extension (ECE) came out to be important prognostic factors in this study.
CONCLUSION: Neoadjuvant chemotherapy is a reasonable alternative to upfront surgery in the management of LABC. Clinicopathological variables such as nodal status, response to chemotherapy, pathological tumor size and presence of ECE had significant impact on disease free survival.

INTRODUCTION

Locally advanced breast cancer (LABC) is defined by presence of a large primary tumor (>5 cm or T3), associated with or without skin or chest-wall involvement (T4) or with fixed (matted) axillary lymph nodes or with disease spread to ipsilateral internal mammary or supraclavicular nodes in the absence of any evidence of distant metastases.[1] LABC accounts for 10-20% in the West,[1] while in India, it accounts for 30-35% of all cases. LABC encompasses a wide spectrum of malignant breast tumors with varying presentation and poses a significant therapeutic challenge. The treatment of LABC has changed dramatically over last few decades. The introduction of neoadjuvant chemotherapy (NACT) in LABC offered us advantages like initiation of early systemic therapy, delivery of drugs through intact vasculature, down-staging of tumors, which makes inoperable tumors operable and renders tumors suitable for breast conserving surgery (BCS).[23] It also helps in vivo assessment of response. National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 and Milan trials have shown that there were no difference in disease free survival (DFS) and overall survival between the patients who had received NACT when compared to the patients who had received postoperative adjuvant chemotherapy.[3] This has led NACT to gain a major foothold in the management of LABC. There are very few Indian studies of NACT in LABC published until date. Keeping this in mind, we have conducted a retrospective analysis to see the outcome of NACT in LABC patients at a tertiary care center.

MATERIALS AND METHODS

We retrospectively reviewed the case files of 148 patients of stage III LABC patients treated with NACT followed by surgery and radiotherapy from January 2006 to December 2010. The pathologic diagnosis was confirmed by fine-needle aspiration cytology or core needle biopsy performed before treatment. Complete Metastatic workup with chest X-ray, ultrasound abdomen, and bone scan of each patient was done. Four to six cycles of NACT were administered at 3 weekly intervals.

Chemotherapy regimens

FAC

5 fluorouracil (FU) - 600 mg/m2 intravenous (iv) day 1.

Adriamycin - 50 mg/m2 iv day 1.

Cyclophosphamide - 600 mg/m2 iv day 1.

AC → T

Adriamycin - 60 mg/m2 iv day 1.

Cyclophosphamide - 600 mg/m2 iv day 1

Paclitaxel - 175 mg/m2 iv day 1

CMF

Cyclophosphamide - 600 mg/m2 iv day 1.

Methotrexate - 40 mg/m2 iv day 1.

5 FU - 600 mg/m2 iv day 1.

Clinical response (CR) to NACT was assessed according to World Health Organization criteria. After surgical resection, a separate evaluation of pathological responses was also done.

Radiotherapy was given to all patients who underwent BCS (40 Gy/16#/3 weeks). Patients with positive or close margins were given boost with Ir 192 implant or electron beam or conformal radiotherapy. Postmastectomy radiation dose was 35 Gy/15# to chest-wall and 40 Gy/15# to the supraclavicular fossa. Tamoxifen or letrozole was given to hormone receptor positive patients for 5 years according to the menopausal status.

RESULTS

Patient characteristics

Median age at presentation was 46 years (range: 22-72 years). Majority of the patients were postmenopausal (57.4%). Tumour stage was T4 in 57.4% patients. 84 (56.7%) patients presented with no axillary or single mobile ipsilateral axillary lymphnode, whereas 64 (43.30%) patients had N2 or N3 disease. Hormone receptor positivity was seen in 55% patients [Table 1].

Table 1

Patient characteristics

Majority of the patients (60.8%) patients received only anthracycline-based chemotherapy and 52 (35.1%) patients received combination of anthracycline and taxane-based chemotherapy with median number of cycles being six. Six patients received CMF based chemotherapy due to preexisting cardiac morbidity (i.e., coronary artery disease in three patients, dilated cardiomyopathy in one patient, systolic dysfunction with ejection fraction <50% in two patients) and of older age. These patients were of >70 years of age and their mean Karnofsky performance status (PS) was 70.

Response to neoadjuvant chemotherapy

Most of the patients (80.4%) responded to NACT either in the form of complete or partial response (PR). Complete CR was seen in18% patients and PR was seen in 62% patients, 13% patients had stable disease (SD) and 7% patients had progressive disease (PD) after NACT. Pathological complete response (pCR) was seen in 24 (16.20%) patients [Table 2]. There was no significant difference in response when anthracycline and taxane-based chemotherapy was compared.

Table 2

Response to NACT

Surgery

Breast conserving surgery was possible in 42 (28.4%) cases. 96 (64.9%) patients underwent modified radical mastectomy. Axillary clearance was done in 92% patients. Most of the patients (78%) underwent axillary dissection up to level II. Previously performing a mastectomy after NACT was our institutional protocol. There was no statistically significant difference in DFS between the patients undergoing BCS and mastectomy. In 10 patients surgery could not be possible due to PD.

Postoperative histopathology findings

Most (82.4%) patients had invasive ductal carcinoma. Only 12 (8.1%) patients had positive margins. Median number of axillary lymphnodes dissected was 11 (range: 3-19). Lymphovascular space invasion was positive in 43 (29.1%) patients and extracapsular extension (ECE) was present in 27 (18.2%) patients.

Pattern of failure

At a median follow-up period of 44 months, 36 patients (24.3%) developed relapse of which six patients developed locoregional recurrence (LRR) while 28 patients developed distant metastases and two patients had recurrence in the contralateral breast. Among six patients with LRR, three patients developed local recurrence, one patient developed axillary lymphnode recurrence, another two developed supraclavicular nodal relapse. Lung, liver and bones were the common sites of distant relapse. Four patients developed brain metastasis of which one developed leptomeningeal metastasis.

Prognostic factors and survival

Patients with N0 or N1 disease had better 5 year DFS when compared to patients with N2 or N3 disease (84% vs. 48%; P = 0.04) [Figure 1]. Different chemotherapy schedules had no significant impact on DFS. Patients who had responded to chemotherapy (CR + PR) had significantly better 5 year DFS than nonresponders (SD + PD) (80% vs. 15% P = 0.02). The patients who had achieved a pathological tumor size of <3 cm had better DFS when compared to patients with pathological tumor size of >3 cm (93% vs. 22% P = 0.03) [Figure 2]. Presence of ECE was also associated with higher distant relapse. 5 year DFS was 24% in patients who had ECE as compared to 89% in patient who had no ECE. (P = 0.025) [Figure 3]. Age, menopausal status, hormone receptor profile, lymphovascular space invasion, margin positivity had no significant impact on DFS as shown in Table 3.

Figure 1

Kaplan–Meier curve showing impact of nodal status on disease free survival

Figure 2

Kaplan–Meier curve showing impact of pathological tumour size on disease free survival

Figure 3

Kaplan–Meier curve showing impact of extracapsular extension on disease free survival

Table 3

Impact of different prognostic factors

DISCUSSION

Neoadjuvant chemotherapy is known to be beneficial for down-staging patients with LABC. There is paucity of literature pertaining to outcome of NACT in LABC in India where majority of breast cancer patients present with advanced disease. The aim of the study was to assess the use of NACT in patients with LABC at an Indian tertiary care center.

The median age of presentation in our study is 46 years, which is quite comparable with other studies. Raina et al.[4] in an early breast cancer study reported median age of 47 years whereas Min et al.[5] showed median age of presentation was 49 years. 42.6% of our patients were premenopausal, which is slightly lower than other studies by Yadav et al.[6] and Chen et al.[7] A study by Raina et al. showed estrogen receptor (ER) positivity of 64%.[8] Western literature reported ER positivity of around 60%. In this retrospective analysis, 55.4% patients were hormone receptor positive, which is similar to other studies.

Median number of NACT cycles used in our patients was six. There is a lot of variation in the number of cycles of chemotherapy that are given in neoadjuvant setting in the literature.[9] Investigators have administered either 3-4 cycles of chemotherapy or chemotherapy was continued up to maximal response.[1011] The advantage of giving chemotherapy up to maximal response is that if the patient has achieved good CR in less than planned cycles, continuation of further chemotherapy consolidates the complete response by maintaining the dose intensity. Another advantage of continuing NACT up to maximal response is that it may be possible that a fixed number of cycles may not be enough to achieve the amount of response necessary to do BCS and if chemotherapy is continued, further regression may continue.[12] Majority of our patients achieved maximal response after six cycles of NACT. Most of the patients (60.8%) received anthracycline based chemotherapy as per institutional protocol. However, with increasing popularity of taxanes considerable amount of patients (35.1%) received combined anthracycline and taxane-based chemotherapy. There was no statistically significant difference in DFS between the two arms. When docetaxel has been compared head on with anthracycline based chemotherapy it seems to show a better response rate in selected patients as reported in a small series.[9] The NSABP trial has shown that use of taxanes with doxorubicin sequentially did show a better response rates in terms of superior partial and complete response both in ER positive and negative patients.[13] 80.4% of our patients responded to NACT (clinical CR + PR) with pathological CR being 16.2%. NSABP-27[13] and a study by Min et al.[5] showed pCR rate after NACT of 26.1% and 20% respectively. Many other studies showed variable pCR ranging from 4% to 40%.[71415] Our study showed a slightly lower pCR possibly because majority of patients received anthracycline based chemotherapy and we did not include patients with early breast cancer.

Breast conserving surgery was possible in 28.4% of cases. The rates reported in literature ranges from 16% to 80%.[6] The rates of BCS after NACT in the present study is comparable to those reported in the literature.[16171819] Such variation can be due to different study population and different chemotherapeutic regimes used. Hence, BCS can be a good option after NACT in LABC patients instead of radical surgery.

When we analyzed different prognostic factors, we found that response to chemotherapy was an important determinant of DFS. Patients who responded to chemotherapy had significantly better DFS when compared with patients who had stable or PD after NACT (80% vs. 15%; P = 0.02). Deo et al. showed similar results in their study.[18] In the present study, prognosis for patients with N0 or N1 disease was favorable compared with patients with advanced nodal disease (5 year DFS 84% vs. 48%; P = 0.04) which was in concordance with the finding described by Giordano.[19]

Pathological tumor size was also an important determinant of prognosis in this study. Min et al. showed pathological tumor stage did not have significant impact on LRR free survival.[5] In a study by Chen et al.[7] it has been seen that 5 year LRR free survival was less in patients who had residual tumor size of >2 cm after NACT as compared to patients who had residual tumor size of <2 cm. The current study showed patients who achieved pathological tumor size of <3 cm had better 5 year DFS than patients who had pathological tumor size of more than 3 cm (5 year DFS 93% vs. 22%; P = 0.03).

Extra capsular extension is another pathological variable which has significant impact on prognosis. Brenner et al.[20] showed borderline significance of ECE in terms of survival, whereas Yadav et al.[6] showed ECE was a significant factor that correlated with distant relapse free survival. We found presence of extensive ECE was associated with decreased 5 year DFS (25% vs. 89%; P = 0.025).

In the present study LRR was seen in 4% patients and ipsilateral breast tumor recurrence (IBTR) was seen only in three patients. The Institut Curie reported IBTR rates of 16% at 5 years and 22% at 10 years for patients who underwent BCS after NACT.[21] Bonadonna et al. reported a 5 year IBTR rate of 7% after BCS and NACT.[22] In addition, Cance et al. recently reported an IBTR rate of 10% among patients with advanced primary tumors treated with BCS after NACT.[23] Most of our patients underwent modified radical mastectomy after NACT which might explain very less IBTR rates in the present study. Patient selection criteria, different therapeutic approaches, type of surgery, chemotherapeutic regimens used are probably the major factors responsible for the variation in published rate of LRR.

The limitation of this study is its retrospective nature and its short follow-up. However BCS rates can be further increased with sequential use of taxanes in the future, which may also help us to get the real picture of locoregional relapse pattern after BCS in LABC.

CONCLUSION

Neoadjuvant chemotherapy should be considered as a reasonable alternative for patients with LABC. NACT contributes to improved operability and makes BCS feasible without jeopardizing overall survival. The present study demonstrates clinicopathological variables such as nodal status, response to chemotherapy, pathological tumor size and presence of ECE had significant impact on DFS.