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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 587-592
 

An analysis of response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer with emphasis on pathological complete response


1 Department of Surgical Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Medical Oncology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
3 Department of Surgical Oncology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
4 Department of Radiation Oncology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India

Date of Web Publication1-Feb-2016

Correspondence Address:
H Narendra
Department of Surgical Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175316

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 » Abstract 

Context: In India, most breast cancer women present at a locally advanced stage. Routine practice in majority of the cancer centers is to administer neo-adjuvant chemotherapy (NACT) followed by loco-regional treatment. Surgery is scheduled after 3 or 4 cycles. The patients who achieve pathological complete response (pCR) are expected do well. Aims: The present study was conducted to analyze our results with NACT, to know pCR rate, to compare pCR rates among various subgroups and to determine the factors which predict pCR. Settings And Design: The study was conducted in a tertiary care university affiliated cancer hospital in South India. Subjects And Methods: All patients with non-metastatic locally advanced breast cancer and agreed by the hospital tumor board to receive NACT were included. At each visit, response was assessed according to RECIST criteria. Re-staging work up and mammography was done prior to surgery. Statistical Analysis Used: Chi square test was used to analyze categorical variables and uni and multivariate analysis were performed to determine the factors predicting pCR rates. Results: A total of 84 patients received NACT. Median age was 46 years (ranged from 28 to 66), 46 patients were premenopausal. Totally 72 patients completed the full course before surgery. Clinical response was complete in 26, partial in 52 and 3 had local progression, one stable and two patient developed distant metastasis. Forty-eight patients underwent modified radical mastectomy and breast could be conserved in 34 patients, pCR rate was 36%. Conclusions: Compared with historical controls particularly from India, we could achieve higher pCR rates.


Keywords: Breast conservation surgery, neo-adjuvant chemotherapy, pathological complete response, surgery for locally advanced breast cancer


How to cite this article:
Narendra H, Thomas J, Ray S, Fernandes D J. An analysis of response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer with emphasis on pathological complete response. Indian J Cancer 2014;51:587-92

How to cite this URL:
Narendra H, Thomas J, Ray S, Fernandes D J. An analysis of response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer with emphasis on pathological complete response. Indian J Cancer [serial online] 2014 [cited 2019 Dec 8];51:587-92. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/587/175316



 » Introduction Top


Breast cancer is the most common cancer among urban women and second among rural women in India. There is a wide gap in the stage of presentation of these patients between urban and rural women. In fact up to 50-70% of the breast cancer patients particularly in regional cancer centers still present with locally advanced stage. [1],[2],[3],[4] World-wide, with the advent of newer chemotherapeutic drugs, biological agents and employment of the multimodality treatment, prognosis of locally advanced breast cancer (LABC) has improved with an expected 5 year survival of up to 63%. [5],[6],[7],[8],[9],[10],[11],[12]

The pre-operative or neo-adjuvant chemotherapy (NACT) has become the initial standard treatment of LABC, followed by surgery, adjuvant chemotherapy and radiotherapy with or without hormonal treatment, usually in that order. Among the various advantages of employing chemotherapy before surgery which have been well-described in the literature, the one which is most relevant to our study is its ability to act as in vivo chemo-sensitivity test. [13],[14],[15],[16] In the majority of the Indian centers as well as other developing nations, where LABC is frequent, surgery is scheduled after initial 3-4 cycles of NACT. [17],[18],[19],[20] We changed our approach following the publication of the guidelines for International Breast Health and Cancer Control Implementation, overview of the Breast Health Global Initiative Global Summit relevant to the care of LABC in low and middle income countries in 2008. [21] This has been reiterated by the recommendations of a more recent international conference on primary systemic chemotherapy in breast cancer. [22] Our approach is to complete the full planned course of chemotherapy before surgery, particularly in responders. This approach is rational as various randomized trials especially in operable breast cancer have shown that the administration of chemotherapy before or after surgery will not change either overall or disease free survival, rather completing the chemotherapy prior to surgery gives additional advantage of breast conservation in larger tumors. [14],[15],[23] Hence, we came out with this study to analyze our results with NACT for LABC, to know the pathological complete response (pCR) rate, to compare pCR rates among various groups, to determine the factors, which predict pCR and to recommend the timing of surgery following NACT.


 » Subjects and Methods Top


This is a prospective hospital based study conducted in a tertiary cancer center affiliated to medical college. All women with biopsy proven LABC (defined as stage III American Joint Committee on Cancer/tumor nodes and metastasis [AJCC/TNM] staging, 7 th edition, 2010) over a 5 year period were included. All patients were evaluated clinically with detailed history, physical examination followed by laboratory tests such as complete blood count, liver and renal function tests. As a part of the hospital protocol the metastatic work up consisted of a chest radiograph, ultrasound abdomen and pelvis and technetium-99m-Methylene diphosphonate bone scintigraphy. All biopsy samples were evaluated with immunohistochemistry staining for expression of estrogen (ER), progesterone (PR) receptors and HER-2/neu over expression. A bilateral mammosonogram was done in all patients except those who had painful or ulcerated lesions. The patients who were diagnosed to harbor metastasis were excluded from the study. All other patients staged to have LABC were referred to medical oncology services for NACT. All patients were assessed for response by clinical examination before starting each new cycle. If the disease is found to be progressing or stable patients were referred for surgery. In those patients who showed response underwent full course of planned chemotherapy before surgery. After surgery patients were planned for external beam radiotherapy to chest wall/breast followed by hormonal treatment if receptor positive.

The surgery was planned after 3 weeks of last chemotherapy once the total counts were above 4000/cmm. Prior to surgery a detailed clinical assessment was done to know the status of disease, a chest radiograph, ultrasonography of the abdomen and pelvis and mammosonogram were repeated. The decision with regard to conserving the breast as per patient's desire was taken in consultation with the hospital multidisciplinary tumor board. The pCR was defined as the absence of invasive cancer in both the breast and dissected axillary nodes. Those patients who received all cycles of chemotherapy prior to surgery were referred to radiation oncology services for radiotherapy and patients who did not complete all cycles received adjuvant chemotherapy followed by irradiation.

Statistical methods

Chi square test was used to analyze categorical variables and uni and multivariate analysis were performed to determine the factors predicting pCR rates.


 » Results Top


A total of 84 patients were diagnosed to have LABC during the study period and referred for NACT, of which 72 patients received the full course of planned chemotherapy before surgery. Twelve patients were operated before completing the full pre-operative chemotherapy for various reasons which are cited in the [Figure 1] above and received adjuvant chemotherapy postoperatively. Of the total 72 patients who received the full course of planned chemotherapy, 2 patients were found to have distant metastasis on pre surgical evaluation and were not operated. Totally 70 patients underwent surgery after completing all the course of chemotherapy. The patient and tumor characteristics are summarized in [Table 1]. The majority of patients were premenopausal (55%), 2 patients had bilateral tumors and most common tumor location was upper and outer followed by multi-quadrant disease. The most common histology was infiltrating ductal carcinoma and the majority of the tumors were receptor positive (49%). Clinically 48% of the patients belonged to AJCC/TNM stage IIIB, 46% to IIIA and only 5 patients to IIIC. The most common chemotherapeutic regimen used was 4 cycles of 3 weekly AC followed by 4 cycles of 3 weekly paclitaxel [Table 2]. The chemotherapy associated side effects included alopecia in all patients, febrile neutropenia in 9 patients, bone marrow suppression in 2 and paclitaxel induced neuropathy in two patients. On pre-surgery evaluation, 93% of the patients had downstaging of the disease of which 29% had complete remission and 64% had partial response. Among the partial responders, 12% had only mammosonographic evidence of the residual disease. Two patients had developed systemic metastasis. Totally 48 patients (57%) underwent modified radical mastectomy and breast could be conserved in the remaining 36 patients (43%). Totally 31 patients (36%, P = 0.027) achieved pCR. At the beginning of the study clinically 82 patients were T4/T3, N + or any T with N2/N3 disease and after NACT only 26 patients had persistent T3/T4 or N2/N3 disease, thus 75% of the patients were down staged [Figure 2]. Of the 73 node positive patients, 47 (64%) became node negative following NACT. Among those who achieved pCR 27 patients (87%) had received full course of chemotherapy before surgery. Further 23 of 31 pCR (74%) were seen in patients who also received taxane. On univariate analysis, among the various factors which are likely to predict the pCR, we could not find any statistically significant association with age <40 years (P = 0.20), menopausal status (21 pCR was seen in 45 premenopausal women, P = 0.055) and hormone receptor status (15 pCR in 35 patients, P = 0.058). The only factor which was associated with predicting the pCR was cT size of the tumor; smaller tumors being more likely to achieve pCR [Table 3]. This association was confirmed on multivariate analysis also (P = 0.017). Further it was also noted that ER/PR negative, HER-2/neu positive tumors are likely to achieve higher pCR (P = 0.058), compared to other receptor subsets [Table 4].
Figure 1: Schema of the study

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Figure 2: Down staging with neo - adjuvant chemotherapy

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Table 1: Patient and tumor characteristics in the study

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Table 2: Summary of the results of the study


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Table 3: Factors predicting pCR


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Table 4: pCR rates by HR status and HER-2/neu overexpression


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 » Discussion Top


The LABC is a disease of neglect in majority of the Indian women. [3] Even with the introduction of multimodality treatment the outcome is dismal. The outcome would be better for those patients who achieve pCR with NACT [13],[15],[22],[23],[24],[25],[26],[27],[28],[29],[30] The pCR rates with the traditional approach of 3-4 cycles of NACT ranges anywhere between 3% and 16% respectively. [13],[28],[31],[32],[33],[34],[35],[36],[37],[38] Higher pCR rates of up to 20-40% can be achieved with the addition of taxanes to anthracyclines [23],[26],[30],[39] and still higher rates of up to 65% are possible with addition of trastuzumab in HER-2/neu over amplified tumors. [40],[41],[42] Many neoadjuvant studies have shown that achieving pCR confers a survival advantage. [13],[42],[43],[44] In a study of 372 LABC patients receiving 4 cycles of doxorubicin based NACT reported from University of Texas MD Anderson Cancer Center, 5 year disease free survival and overall survival were significantly higher inpatients who had pCR compared with patients who had less than pCR. [13]

In the present study where majority of the patients completed chemotherapy prior to surgery, the pCR rate was 36%, which is much higher compared with other studies from India. [18] Such a higher rate could be attributed to the consolidation of the response achieved by initial anthracycline based NACT with sequential taxane and additional cycles of chemotherapy. In a similar study from India, Parmar et al. noted an increase in pCR rates from 4.3% to 10.5% when 4 or more cycles of NACT was delivered in 1402 women with LABC. [18] Steger et al. in their study have reported an 11% increase in pCR rates from 7.7% to 18.6% with 6 cycles compared to 3 cycles. [45] The factors which can help the clinician to predict pCR rates reported in various studies include young age, ER/PR negativity, high Ki 67 score, high nuclear grade and smaller tumor size, ductal histology versus pure lobular carcinoma and number of NACT cycles. [5],[13],[18],[22],[36],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56] The pCR is more likely in hormone receptor negative, HER-2 overexpressing tumors. [26],[57] In our study only cT size was found to be statistically significant in predicting pCR [Table 3]. Some of the studies have focused on developing a nomogram to predict pCR rates and metastasis free survival by incorporating some of these factors in patients undergoing pre-operative chemotherapy. A pCR nomogram based on clinical stage (TNM), hormone receptor status, nuclear grade and number of pre-operative chemotherapy cycles has been developed. By using this, when the predicted pCR was 38% or more, actual pCR rate was 85% and if predicted rate was between 14% and 38%, actual rate was 50% with weekly and 27% with 3-weekly schedule of paclitaxel following anthracycline based NACT. Patients unlikely to achieve pCR to anthracylines remain at low probability for pCR, even after inclusion of paclitaxel. The scheduling of paclitaxel (weekly vs. 3 weekly) made difference only in the intermediate chemo sensitivity group. Such nomograms may help in deciding about the exact number of pre-operative cycles, chemotherapeutic angents and scheduling of the drugs. [58]

The importance of achieving pCR in LABC cannot be overemphasized. Recently achieving pCR has become the primary end point of many of the NACT trials. [16],[22],[26],[44] One word of caution is that though patients who achieve pCR would do better in the long run, they carry high risk of relapse up to 5% local and 12% at distant sites. [13],[59] Hence these patients need continued surveillance for life long. Before the final recommendations regarding the timing of surgery longer follow-up of these patients are needed. [13] Another area of concern which is also the disadvantage of NACT is the development of drug resistance as well as the response of primary and metastatic sites may not be similar. [60] In the present study, even though 2 patients appeared clinically to respond well to NACT, they had developed systemic metastasis before surgery, one in brain and the other in lungs. It is less likely that the initial staging evaluation would have missed them as they were asymptomatic for almost 6 months of chemotherapy regimen and later became symptomatic. This would call in to question whether pCR to NACT simply selects a group of patients who have biologically predetermined favorable tumor or does really NACT alters the course of the disease as suggested by an earlier study. [13] The answer needs to be found with well-designed randomized trials.

The management of patients who progress on NACT has limited options. In our study, a total of 5 patients (6%) progressed on NACT. For patients who progress, regimen can be changed over to non-cross-resistant drugs and observed for response. For patients with stable disease or local progression surgery if feasible can be offered or radiotherapy could be considered. In our study of the 5 patients progressed, 3 had local progression who were offered surgery and 2 developed systemic disease and surgery was avoided. The reported frequency of progressive disease on NACT is around 3%. The early identification of this subset of patients through frequent clinical assessment may allow for change of the ineffective regimen to potentially beneficial therapies such as non-cross resistant chemotherapy, surgery if feasible and/or radiotherapy. [44],[52]

Apart from the higher pCR rates observed in our study, other interesting findings need to be highlighted. The overall clinical response rate was 93% and 75% of the tumors were downstaged with chemotherapy. Nearly 64% of patients with node positive disease were rendered node negative. This group of patients is expected to do better next to the pCR group. [4],[16] Though it is reported that the patients who were rendered node negative with NACT actually harbor occult metastasis on immunohistochemical evaluation in 16%, this will not affect either overall or disease free survival. [61] Another interesting finding is that we could conserve breast in 43% of the patients which is exceptional considering the initial advanced stage at presentation. The MD Anderson study cited earlier reported a breast conservation (segmental mastectomy) rate of 29%. [13] A successful breast conservation rate of 45% has been reported by another NACT study by Cance et al. in a group of 62 non-inflammatory LABC patients. [6],[13],[30] In a large study of 1402 LABC patients from India, a breast conservation of 30% were reported with anthracyline based NACT. [4] For those patients who respond with less than a pCR do not appear to benefit from further adjuvant chemotherapy following surgery. [28] In a study of 193 LABC patients by Thomas et al., pCR rate with neoadjuvant cyclophosphamide, vincristine, doxorubicin and prednisone (CAVP) was 12.2%. When 51 of the 106 patients who did not achieve pCR, were randomized to receive additional CAVP and rest to vinblastine, methotrexate, leucovorin and fluorouracil, there was no statistically significant difference in both disease-free and overall survival, suggesting little benefit to adjuvant chemotherapy when NACT fails to induce pCR. [28] Hence there is no evidence to suggest additional adjuvant therapy for patients who complete standard neoadjuvant therapy, even if pCR is not achieved.


 » Conclusion Top


We believe that neoadjuvant therapy for breast cancer needs to be differentiated into two different situations i.e. one for early breast cancer and the other for LABC. The vast majority of the level one evidence in the form of randomized trials is available for the former group. For LABC in particular the randomized comparison between neoadjuvant and adjuvant approach is not available till date. [15] Until such evidences are available, it is reasonable to complete all the chemotherapy cycles including taxane in patients who show response to initial cycles of anthracycline chemotherapy and to add trastuzumab for her 2nu overexpressing tumors prior to surgery. This is particularly true for smaller tumors and hormone receptor negative tumors. [22] Further studies are needed to focus on the management of patients who progress on chemotherapy as well as for patients who achieve less than pCR.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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