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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 343-346
 

Retrospective study of efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive locally advanced and oligometastatic breast cancer: An Indian experience


1 Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
2 Department of Surgical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Radiotherapy, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. A Gogia
Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_152_17

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 » Abstract 

BACKGROUND: The neoadjuvant chemotherapy in HER2-positive breast cancer consists of a chemotherapy backbone and HER2-directed therapy. The increase in cardiotoxicity by the use of trastuzumab with an anthracycline-based regimen has led to the use of nonanthracycline-based alternative regimens. The docetaxel, carboplatin, and trastuzumab (TCH) are one such regimen. The efficacy and toxicity of this regimen have not been widely studied in Indian patients. AIMS: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH regimen in locally advanced and oligometastatic HER2-positive breast cancer in Indian patients. METHODOLOGY: The hospital records between January 2014 and December 2016 were reviewed to identify patients with locally advanced and oligometastatic HER2-positive breast cancer treated with uniform 3-weekly neoadjuvant chemotherapy protocol-containing docetaxel (75 mg/m2), carboplatin (AUC = 6), and trastuzumab (8 mg/kg loading followed by 6 mg/kg) (TCH). The primary outcome was the pathologic complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymphnode. RESULTS: Thirty-two patients with mean age 46 years met our inclusion criteria, of these 24 patients had locally advanced breast cancer, and eight patients had oligometastatic breast cancer. 13 (40.6%) patients had hormone-positive breast cancer. The objective response rate as assessed clinically was 100%, and pCR rate was 36.3%. The patients with oligometastatic breast cancer also showed a good response to chemotherapy with three patients showing pCR and four patients showing resolution disease at metastatic sites. The patients experienced very few Grade III/IV toxicities, and no patient had clinical congestive heart failure. CONCLUSION: The TCH protocol is an efficacious neoadjuvant chemotherapy regimen for locally advanced and oligometastatic breast cancer and is safe and well tolerated in this population.


Keywords: HER2/neu-positive breast cancer, neoadjuvant chemotherapy, nonanthracycline regimen, oligometastatic breast cancer


How to cite this article:
Tiwari A, Gogia A, Deo S, Shukla N K, Mathur S, Sharma D N. Retrospective study of efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive locally advanced and oligometastatic breast cancer: An Indian experience. Indian J Cancer 2017;54:343-6

How to cite this URL:
Tiwari A, Gogia A, Deo S, Shukla N K, Mathur S, Sharma D N. Retrospective study of efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive locally advanced and oligometastatic breast cancer: An Indian experience. Indian J Cancer [serial online] 2017 [cited 2019 Feb 23];54:343-6. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/343/219541



 » Introduction Top


HER2/neu is overexpressed in 20%–25% of the breast cancer in India and Western population.[1],[2] These tumors are more aggressive and have higher rates of metastasis and poor survival as compared to its hormone receptor-positive counterpart.[3]

The locally advanced breast cancer is treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. The neoadjuvant chemotherapy for HER2-positve breast cancer contains a chemotherapy backbone and trastuzumab ± pertuzumab. The use of trastuzumab has shown to improve disease-free survival and overall survival.[4] This improvement in the outcomes has come at the cost of increased cardiotoxicity apart from the other side effects of this drug.[4],[5] This toxicity is compounded when it is used concomitant with an anthracycline-containing chemotherapy regimen in adjuvant and neoadjuvant setting. This shortfall led the path to the use of nonanthracycline-based regimen. The addition of carboplatin and docetaxel to trastuzumab (TCH) was shown to have synergistic effect in vitro studies.[6],[7] This regimen has also shown lesser incidence of acute toxicity, cardiotoxicity, and secondary acute leukemia with equivalent outcomes in adjuvant setting for HER2-positive breast cancer.[8] Although there has been no Phase III randomized study evaluating the TCH regimen in neoadjuvant setting as compared to anthracycline-based regimen, the evidence of its use stems from the data of this regimen in adjuvant setting and other Phase II and retrospective studies.[9],[10],[11],[12],[13],[14]

Here, we evaluate the pathologic complete response (pCR) rates and toxicity profile of patients with HER2-positive locally advanced and oligometastatic breast cancer treated with uniform TCH protocol in a tertiary care center in North India.


 » Methodology Top


The records of patients registered in breast cancer clinic, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (New Delhi), between January 1, 2014, and December 31, 2016, was reviewed. The patients with inoperable locally advanced breast cancer and patients willing for breast conservation therapy but not amenable for the same were referred for neoadjuvant chemotherapy. All patients underwent detailed clinical examination and breast imaging (mammography). The metastatic workup was done in all patients. The HER2/neu overexpression was defined as positive immunohistochemistry (IHC 3+) or positive fluorescence in situ hybridization (FISH). FISH was done only in patients who had intermediate IHC positive (IHC 2+). The ASCO-CAP HER2 test guideline recommendations were used to interpret results of FISH. An HER2/CEP17 ratio ≥2 or ratio <2.0 with average HER2 copy number ≥6 was considered positive. The hormone status was assessed by IHC. The tumors with either estrogen receptor- or progesterone receptor-positive were taken as hormonal receptor-positive. The degree of positivity was scored according to the Allred score.

The patients with HER2/neu overexpressing breast cancer (locally advanced and oligometastatic breast cancer) who were treated with a uniform TCH protocol were included in the study. The oligometastatic disease was defined as less than three sites of metastasis with any metastasis <3 cm.

The patients were treated with trastuzumab (8 mg/kg loading followed by 6 mg/kg), carboplatin (AUC = 6) and docetaxel (75 mg/m 2) q 21 days for six cycles. These patients were evaluated clinically at the end of every cycle for response and any sign of progression. The patients who progressed were referred for surgery, and the remaining patients completed six cycles of chemotherapy. The patients were assessed after six cycles of chemotherapy for mastectomy or breast conservation therapy, and the surgery was performed after the patient recovered from the toxicity of the last cycle. The patients with oligometastatic breast cancer also underwent a whole-body positron emission tomography-computed tomography (PET-CT) after six cycles of chemotherapy. The postoperative specimen was evaluated for a pathologic response. The pCR was defined as the absence of residual invasive or in situ cancer in breast or axilla. The patients received adjuvant trastuzumab maintenance therapy for 1 year and adjuvant hormonal therapy and radiotherapy as applicable. The toxicity was graded according to CTCAE version 4.

The primary outcome measure of this study is pCR rate in patients with HER2 + breast cancer (locally advanced or oligometastatic breast cancer) undergoing neo-adjuvant chemotherapy with TCH protocol. The secondary outcomes were toxicity and number of patients undergoing breast conservation surgery (BCS).


 » Results Top


A total of 32 patients with locally advanced and oligometastatic HER2/neu-positive breast cancer were treated with TCH protocol during January 2014–December 2016. The baseline characteristics of these patients are described in [Table 1]. The majority of patients had nonmetastatic locally advanced breast cancer (24 patients), of these a large majority of patients (15 [62.5%]) had T4 disease. The patients with nonmetastatic breast cancer had a high nodal disease burden with 14 (58.3%) patients showing N2 (10/15) or N3 (4/15) disease. Eight patients had oligometastatic breast, In this subgroup, the most common site of metastasis was bone with five of the eight patients having bone metastasis and one patient each having lung and liver metastasis. Of the total patients, seven patients with locally advanced breast cancer and two patients with oligometastatic breast cancer were either undergoing chemotherapy or awaiting surgery till the last follow-up (February 28, 2017).
Table 1: Baseline characteristics of the patients

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The median duration of follow-up was 270 (166–431) days. A clinical complete response was seen in 10 (45.4%) patients, and a clinical partial response was seen in 12 (54.6%) patients. The overall response rate was 100%. The pCR was reported in eight patients (36.3%) of the total 22 patients (including locally advanced and oligometastatic breast cancer) who underwent surgery [Table 2]. This included three patients in the oligometastatic breast cancer subgroup. Of the 22 patients who underwent surgery, 14 patients were hormone receptor-positive and 8 patients were hormone receptor-negative. There was no significant difference in the proportion of patients with hormone receptor-positive HER2/neu overexpressing breast cancer in patients who achieved or did not achieve a pCR (P = 1.0). The BCS was done in six (27.2%) of the 22 patients who had underwent surgery till the last follow-up. In the oligometastatic disease, four of the six patients who completed therapy reported a complete resolution of the metastatic sites as assessed by whole-body PET-CT scan. In our study population, three patients relapsed and one patient had progression while on therapy (treatment was discontinued in view of acute ischemic stroke), two of these four patients had oligometastatic breast cancer.
Table 2: Pathologic characteristics postneoadjuvant chemotherapy

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The Grade III and Grade IV toxicity associated with this protocol were minimal [Table 3]. The patients were able to receive all the planned cycles of chemotherapy except one patient who developed acute ischemic stroke after 4 cycles and did not receive further chemotherapy; and hence, it was well tolerated.
Table 3: Toxicity profile of patients

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 » Discussion Top


The pCR has been shown to correlate with long-term outcomes such as disease-free survival and overall survival and hence is taken as a surrogate marker to evaluate the long-term outcomes of a chemotherapy regimen.[15] This correlation is the strongest in the triple negative and Her2/neu overexpressing tumors.[16] The pCR rate in our series was 36.3%. This pCR rate is lower to the pCR rate reported in various series.[10],[11],[12],[13] The HER2/neu overexpressing breast cancer is a mixed bag of tumors genetically, and the response to chemotherapy is better determined by the molecular subtype such that the pCR rate is better in HER2-enriched type than the luminal A/B.[17] A low response to chemotherapy is also seen in tumors that have activating mutations of PIK3CA and low-tumor infiltrating lymphocytes.[18],[19],[20] Patients with hormone receptor-positive tumors have shown to have poor response to chemotherapy. We did not find a difference in pCR rate based on hormone receptor status, but it is of note that our sample size is small to detect this difference. It is possible that either or a combination of above-mentioned factors may contribute to the low-pCR rate in our study population.

The overall response rate in our series was high; this is expected in a group of patients with HER2-overexpressing breast cancer treated with this protocol. This high response rate is corroborated with the finding of other studies using TCH protocol in neoadjuvant setting.[10],[12]

It is also notable that though all our patients were either inoperable or not suitable for BCS at the baseline, 6 (27.2%) patients were able to undergo a BCS after the completion of neoadjuvant chemotherapy. Although this rate of BCS is low as compared to the Western population despite of the high rate of response rate.[11] The difference might be due to the difference in the distribution of stage of breast cancer in these studies with most patients in the latter having Stage II disease.

The regimen was safe and well tolerated with few Grade III/IV toxicities. All the patients were able to complete the planned number of chemotherapy cycles except one patient who developed ischemic stroke and could not be given further therapy beyond cycle 4 and then soon progressed. None of the patients developed clinical congestive heart failure during the follow-up period. The safety of this regimen and reduced cardiac complication has also been demonstrated in the previous studies in adjuvant and neoadjuvant setting.[10],[12] It is this low risk of complication that helps this regimen score over its anthracycline-containing regimen.

The patients with oligometastatic breast cancer had bone as the most common site of metastasis, the other site of metastasis was liver and lungs. This subgroup also reported a high pCR rate and resolution of metastatic sites. It is also noteworthy that all patients in this subgroup also completed their planned therapy and had minimal toxicity. This suggests that it is a prudent option to treat patients with HER2/neu-positive oligometastatic breast cancer with TCH protocol with curative intent.

This study is limited by its retrospective design, small number, and short follow-up period. Even with these shortcomings, it gives us an insight in the treatment and response of TCH regimen in patients with HER2/neu-positive breast cancer, including oligometastatic breast cancer. It shows that TCH is an efficacious and safe regimen for patients with this subgroup of breast cancer.


 » Conclusion Top


The findings of this study, especially the outcomes in oligometastatic breast cancer should be evaluated and confirmed in a prospective study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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Gogia A, Raina V, Deo SV, Shukla NK, Mohanti BK, Sharma DN. Taxane and anthracycline based neoadjuvant chemotherapy for locally advanced breast cancer: Institutional experience. Asian Pac J Cancer Prev 2014;15:1989-92.  Back to cited text no. 1
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Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-12.  Back to cited text no. 2
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Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.  Back to cited text no. 3
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Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr., et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014;32:3744-52.  Back to cited text no. 4
    
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De Iuliis F, Salerno G, Corvino R, D'Aniello D, Cefalì K, Taglieri L, et al. Anthracycline-free neoadjuvant chemotherapy ensures higher rates of pathologic complete response in breast cancer. Clin Breast Cancer 2017;17:34-40.  Back to cited text no. 9
    
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Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D, et al. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: Results of the GETN(A)-1 trial. J Clin Oncol 2007;25:2678-84.  Back to cited text no. 12
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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