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Table of Contents
REAL WORLD DATA
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 69-73

Short-course adjuvant trastuzumab in breast cancer: Experience from a tertiary cancer center in rural India


1 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Kannur, Kerala, India
2 Department of Radiation Oncology, Malabar Cancer Centre, Kannur, Kerala, India
3 Department of Surgical Oncology, Malabar Cancer Centre, Kannur, Kerala, India

Date of Submission28-Nov-2019
Date of Decision04-Dec-2019
Date of Acceptance07-Dec-2019
Date of Web Publication24-Feb-2020

Correspondence Address:
Praveen Kumar Shenoy
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalassery, Kannur - 670 103, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_110_19

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  Abstract 


Introduction: Majority of the patients in low-to-middle income countries (LMICs) have no access to adjuvant trastuzumab due to financial constraints. Short-course (9 weeks) schedule of trastuzumab is a feasible alternative in this setting. The objective of this study was to assess the feasibility and outcomes of adjuvant short-course trastuzumab in patients with breast cancer treated at our center.
Materials and Methods: This was a retrospective study conducted in a tertiary cancer center in South India. Case records of all patients who received short-course (9 weeks) adjuvant trastuzumab from June 2014 to December 2016 were reviewed. Baseline characteristics, treatment details, and outcomes were analyzed.
Results: During the study, 129 patients received short-course trastuzumab. The median age was 50 years (range, 30–74 years). Majority of the patients were postmenopausal (64%). The most common histology was infiltrating ductal carcinoma; 57% had Grade 2 disease. The most common chemotherapy regimen used was doxorubicin + cyclophosphamide (AC), followed by weekly paclitaxel (n = 110, 86%) and docetaxel + cyclophosphamide (TC) (n = 17, 13%). Majority of the patients (n = 120, 93%) had T1 or T2 disease and were node-negative (n = 62, 57%). Sixty-two patients (48%) had hormone receptor-positive disease. One hundred and eight patients (84%) underwent modified radical mastectomy, and the rest had breast conservation surgery. At a median follow-up of 29 months, the 3-year overall survival (OS) was 98%; the median OS was not reached. The 3-year disease-free survival (DFS) was 97.4%; the median DFS was not reached. The regimen was well tolerated and none of the patients developed symptomatic cardiac failure.
Conclusions: Our study shows that a 9-week short course of trastuzumab is a feasible strategy in a resource-limited setting and can lead to promising outcomes, especially in early breast cancer.

Keywords: Breast cancer, India, short course, trastuzumab, LMIC, Her2, BRCA


How to cite this article:
Manuprasad A, Shenoy PK, Jones J, Vinin N V, Dharmarajan A, Muttath G. Short-course adjuvant trastuzumab in breast cancer: Experience from a tertiary cancer center in rural India. Cancer Res Stat Treat 2020;3:69-73

How to cite this URL:
Manuprasad A, Shenoy PK, Jones J, Vinin N V, Dharmarajan A, Muttath G. Short-course adjuvant trastuzumab in breast cancer: Experience from a tertiary cancer center in rural India. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Apr 10];3:69-73. Available from: http://www.crstonline.com/text.asp?2020/3/1/69/279069




  Introduction Top


Breast cancer is the most common malignancy in women globally as well as in India. It accounts for 27% of all cancers in women and is the most common cause of mortality as per data from GLOBOCAN 2018.[1] Among the subtypes of breast cancers, human epidermal growth factor receptor 2 (HER2)-positive breast cancer constitutes 25% of all subtypes. It is associated with a high risk of relapse and death from metastatic disease.[2] The use of the monoclonal anti-HER2 antibody, trastuzumab, in the metastatic setting led to a survival benefit with a median overall survival (OS) of 25 months. Later on, trastuzumab was found to improve survival in the adjuvant setting as well.[3] Four major randomized controlled trials have definitively shown the benefit of trastuzumab (3-weekly) administered for 1 year, both in terms of disease-free survival (DFS) and OS.[4],[5],[6] Both cost-effectiveness and cardiac safety concerns led to attempts at reducing the duration of trastuzumab, especially in early breast cancer. The FinHer trial with 232 patients showed a survival benefit from 9 weeks of trastuzumab in early breast cancer.[7] Although there is a growing interest in using less trastuzumab in breast cancer, definite recommendations are lacking in this regard. The Short-HER trial which compared 9 weeks to 1 year of trastuzumab failed to prove the noninferiority of the shorter regime but showed significantly less cardiotoxicity and similar DFS in the low-risk group.[8] Apart from the FinHER trial, multiple retrospective studies and meta-analyses also reported the efficacy of short-course trastuzumab. The short 9-week trastuzumab regimen can be considered as a cost-effective strategy in the resource limited setting.

In India, the cost is a major limiting factor in administering trastuzumab for 1 year. One report from India showed that about two-thirds of the patients could not receive adjuvant trastuzumab; these patients had a significantly inferior survival.[9] Although there is evidence to show noninferiority of trastuzumab for 6 months in early breast cancer, even that may not be feasible in resource-limited countries like India.[10],[11] In this situation, the 9-week schedule used in the FinHer trial can be considered as an attractive alternative.[7],[12] However, there are limited published data regarding the outcomes of this regimen from low-middle income countries (LMICs). Here, we share our preliminary experience with adjuvant trastuzumab as a 9-week schedule and evaluate the feasibility and survival outcomes.


  Materials and Methods Top


This was a retrospective study and was approved by the Institutional Review Board (IRB) of Malabar Cancer Centre (IRB No. 1616/IRB-SRC/13/MCC/11-11-2017/3) [Supplementary Appendix 1]. All patients with HER2-positive non-metastatic breast cancer who received adjuvant short-course (9 weeks) trastuzumab from June 2014 to December 2016 were included in the study. Patients were identified from the daycare register, and the case records were retrieved and reviewed. Patients with locally advanced breast cancer who received neoadjuvant trastuzumab were excluded from the study. The primary objective was to study the efficacy and toxicity of short-course adjuvant trastuzumab in our patients [Figure 1]. As per the policy of our IRB, written informed consent is not required for retrospective studies. The study was not registered in a public clinical trials registry, as it was a retrospective study. No funding was obtained for the study. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki, principles of good clinical practice, and the guidelines established by the Indian Council of Medical Research.
Figure 1: Adjuvant short-course trastuzumab in breast cancer-experience from a tertiary cancer center in rural India-Flow diagram showing study schema

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At our institute, all patients with HER2-positive breast cancer after modified radical mastectomy (MRM) or breast conservation surgery (BCS) received adjuvant chemotherapy (4 cycles of doxorubicin + cyclophosphamide [AC] followed by 12 weekly cycles of paclitaxel) or (docetaxel/cyclophosphamide [TC]). Along with estrogen receptor/progesterone receptor studies, immunohistochemistry (IHC) for HER2/neu was also part of the workup. HER2-positivity was established by either IHC 3+ or fluorescence in situ hybridization (FISH) (done if IHC was 2+).[13] All HER2-positive patients were offered adjuvant therapy with 1 year of trastuzumab. Patients who could not afford the standard treatment were given 9 weeks of trastuzumab. Trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) was started after 4 cycles of AC chemotherapy along with weekly paclitaxel or with TC chemotherapy. A baseline echocardiogram was done for all the patients. Patients were monitored regularly for toxicity. Patients underwent clinical examination every visit and blood counts and biochemical investigations, including random blood sugar, renal function tests, and liver function tests every 3 weeks. After completion of 9 weeks of trastuzumab, they received the remaining chemotherapy and radiation or hormonal therapy depending on the stage and receptor status. Hormonal therapy used was letrozole for postmenopausal women (for 5 years) and tamoxifen for premenopausal women (for 10 years).

Statistical analysis

Statistical analysis was done using SPSS Version 20 (IBM Corp., Armonk, NY, USA). Baseline characteristics, disease characteristics, toxicity, and outcomes were recorded. Survival was calculated as per Kaplan–Meier analysis.[14] DFS was defined as the duration from the date of surgery (MRM/BCS) to the date of locoregional or distant failure. OS was defined as the duration from the date of surgery to the date of death due to any cause. The follow-up was calculated as the duration between the dates of surgery to the date of last hospital visit; patients on 6-monthly follow-up were called telephonically to update the survival. All patients were included in the analysis, as per the 'intention-to-treat' principle.


  Results Top


Baseline characteristics

During the study, 129 patients received short-course adjuvant trastuzumab. The median age was 50 years (range, 30–74 years). Majority of the patients were postmenopausal (64%). The most common histology was infiltrating ductal carcinoma; 57% had Grade 2 disease [Table 1]. All the patients availed trastuzumab utilizing funds from government support programs such as government-sponsored insurance or health assurance schemes by the state government, namely Karunya Benevolent Fund and Sukrutham scheme.[14],[15]
Table 1: Baseline characteristics of patients with nonmetastatic breast cancer who received adjuvant short-course trastuzumab (n=129)

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Treatment characteristics [Table 1]

The most common chemotherapy regimen used was AC followed by weekly paclitaxel (n = 110, 86%). The other regimen used was TC (n = 17, 13%). Two patients (1.5%) received 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) followed by docetaxel. Five patients (4%) received chemotherapy with AC as neoadjuvant treatment since the FISH report was not available at the time of treatment initiation. Majority of the patients underwent MRM (n = 108, 84%). BCS was done in 21 (16%) patients. All patients post-BCS and those with node-positive disease after MRM received adjuvant radiation (n = 83, 65%). Sixty-three patients (49%) received adjuvant hormonal therapy based on the menopausal status.

Efficacy and toxicity

None of the patients were lost to follow-up. At a median follow-up of 29 months, the 3-year OS was 98%; median OS was not reached [Figure 2]. Three-year DFS was 97.4% and median DFS was not reached [Figure 2]. Three (2%) patients had disease recurrence; one patient (0.8%) had bone-only metastasis, and two others (1.5%) had bone along with visceral metastasis (liver, lung, and brain). One patient (0.8%) developed a second malignancy in the form of periampullary carcinoma. One patient (0.8%) died due to progressive disease and another patient due to hepatic failure, cause of which could not be established.
Figure 2: Kaplan–Meier estimates of (a) disease-free survival and (b) overall survival in patients who received adjuvant short-course trastuzumab

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Trastuzumab was generally well tolerated in our patients. None of the patients developed symptomatic cardiac failure or significant allergic reaction. Three patients (2%) could not complete 9 weeks of trastuzumab. One patient developed hepatotoxicity after 4 cycles, another had pneumonitis after 5 doses and the third patient had poor tolerance with Grade 3 hyponatremia after 6 doses. Three patients (2.3%) had Grade 3 neuropathy related to weekly paclitaxel; paclitaxel was discontinued in these patients. Other Grade 3/4 toxicities included neutropenia (n = 4, 3%), hyponatremia (n = 2, 1.5%), hepatotoxicity (n = 1, 0.8%), and febrile neutropenia requiring hospitalization was seen in 3 patients (2.3%).


  Discussion Top


Although the survival of breast cancer patients has improved over time, even in developing countries like India, improving the outcomes of HER2-positive breast cancer remains a challenge due to resource constraints. One year of trastuzumab, which is considered as the standard adjuvant treatment, is not accessible to majority of the patients due to cost issues. We present the largest report of short-course adjuvant trastuzumab from India. Our experience at a tertiary cancer center within the public sector highlights the fact that the 9-week schedule is a feasible strategy in our country and can produce favorable outcomes, especially in patients with early breast cancer. Most of our patients had early breast cancer and they received trastuzumab in combination with standard chemotherapeutic regimens. Trastuzumab was well tolerated in our patients with none of the patients developing symptomatic cardiac failure.

Patients with locally advanced breast cancer received neoadjuvant trastuzumab as per the institutional protocol and were not included in the present study. Hence, over 90% of the patients in our study had T1 or T2 disease and about 50% had node-negative disease. Only a minority of our patients underwent BCS despite having early breast cancer similar to other published literature from India.[16] Most of our patients received anthracyclines and taxanes as adjuvant chemotherapy. In older patients, short-course trastuzumab was also easily combined with the TC regimen. In another Indian study, trastuzumab was combined with docetaxel followed by FAC.[17]

Our study population had a 3-year OS and DFS of 98% and 97%. These results are comparable to other studies in patients with early-stage breast cancer. The APT trial which included only patients with node-negative and <3 cm tumors reported 3-year invasive DFS of 98.7%. Although the trial used less intensive chemotherapy in the form of weekly paclitaxel, trastuzumab was given for 1 year.[18] The results were comparable or better than those from other studies using short-course trastuzumab. Previous Indian studies showed significantly lower survival for patients with HER2-positive disease probably due to lack of access to trastuzumab.[19] In a report from a tertiary cancer center in India, the 5-year OS was only 42% in those who did not receive trastuzumab compared to 90% in those who received 3-weekly trastuzumab along with chemotherapy. However, in that study, only 36% of the patients could receive trastuzumab due to financial constraints.[9] Short-course trastuzumab also showed better survival compared to historical controls in another study from India though the median follow-up was only 1 year.[20] In an observational study from the Turkish Oncology Group, the 3-year DFS was similar between the 9-week and 1-year schedule (88.7% vs. 86%) and was comparable to our result.[21] Another report from 8 centers in Turkey showed a 3-year DFS of 90% and 85% and 3-year OS of 96% and 97% for 9 weeks and 1-year schedule trastuzumab, respectively.[22]

Weekly trastuzumab was well-tolerated in our patients. None of the patients experienced any symptomatic cardiotoxicity despite the majority receiving anthracyclines the median age being 50 years, and about 20% having other medical comorbidities. Our study also confirms the lower cardiotoxicity risk with short-course trastuzumab as has been noted in other trials and studies. The Indian study which reported outcomes of 3-weekly trastuzumab reported Grade 2 diastolic dysfunction in 9% of the patients.[9] Despite the common chemotherapy-related toxicities, pulmonary complications were seen in few patients probably related to taxanes. The occurrence of paclitaxel neuropathy was also similar to other reports.

The limiting factor in the use of trastuzumab in a developing country is the cost. In a report from China, of about 5000 patients from multiple centers, only 30% could receive trastuzumab. The most important factor correlating with the use of trastuzumab was insurance coverage.[23] The major obstacle to our patients receiving 1-year trastuzumab was economic constraints. All our patients could receive short-course trastuzumab through government support programs. This clearly shows that even in a resource-limited setting, the 9-week schedule of trastuzumab can be offered by making use of government support schemes. As reported by Li et al., there can be great disparities in the use of trastuzumab within the same country based on the availability of resources.[23] Our real-world data also show favorable outcomes with short-course trastuzumab; therefore, better allocation of resources to ensure access to this drug can save many lives.[24]

Our study had limitations in the form of retrospective design with small number of patients and short follow-up. We did not have a comparator arm with either no trastuzumab or 3-weekly trastuzumab. We included only patients who received weekly trastuzumab; therefore, information of all patients with HER2-positive breast cancer who did not receive any schedule of adjuvant trastuzumab could not be obtained. Asymptomatic patients on 9-week schedule did not undergo periodic echocardiographic evaluation unlike patients on the 3-weekly trastuzumab; therefore, the true incidence of asymptomatic decline in ejection fraction is not known.


  Conclusions Top


Our study shows that short-course trastuzumab (9 weeks) is a feasible option in a resource-limited setting and can produce favorable outcomes, especially in early breast cancer. The regime is well tolerated and can be combined with standard chemotherapy protocols in our population. Making this drug available through government support programs may help to improve the survival of HER2-positive breast cancer in LMICs like India, where 6 months or 1-year schedule of trastuzumab is not accessible to a majority of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Appendix Top


Supplementary Appendix 1: Study Protocol

Short-course adjuvant Trastuzumab: Single Institution Experience from India

PI-Dr. A. Manuprasad, Dr. Praveen Kumar Shenoy

Co PI-Dr. Adarsh D, Dr. Vinin N, Dr. Joneetha J, Dr. Geetha M


  Introduction Top


Human epidermal growth factor receptor 2 (HER-2) positive constitute 25% of all subtypes of breast cancer. Major randomized trials clearly established the benefit with 1 year of adjuvant trastuzumab and it is a standard practice as per all treatment guidelines. However, in developing countries like India, cost is a major limiting factor in administering trastuzumab for 1 year. In this situation, 9 weeks' schedule used in FinHer trial can be considered as an attractive alternative. However, there is limited published data regarding the same from India. We want to report our experience with adjuvant Herceptin as 9 weeks' schedule.

Literature review

HER2-positive breast cancer represent aggressive subtype of breast cancer associated with high risk of relapse and death from metastatic disease.[1] HER2 neu positivity is established by IHC of 3+ or by fluorescence in situ hybridization (FISH) measurement of a HER2 gene copy number of six or more or a HER2/CEP17 ratio of 2.0 or greater.[2] The use of monoclonal anti-HER2 antibody, trastuzumab in metastatic setting showed survival benefit with median overall survival of 25 months and later it was used in adjuvant setting. Four major randomized controlled trials have clearly shown the benefit with Trastuzumab (3 weekly) for 1 year both in terms of DFS and OS.[3],[4],[5] Also in FINHER trial before anthracycline-based chemotherapy, patients received vinorelbine or docetaxel with or without 9 weeks of trastuzumab.[6],[7] They showed that short-course trastuzumab is also beneficial with HR for DFS being 0.65 and OS 0.55. However, compared to studies of 1-year duration, it was a smaller study with 232 patients. Although comparison of 6 month versus 1 year trastuzumab showed inferiority of shorter duration, there are multiple retrospective studies which showed equivalent result with 9 weeks and 1 year schedule.[8] Cardiotoxicity was also significantly less in short duration schedule.

In India, where breast cancer incidence is on the rise, HER2 neu positivity is seen around 30% of the patients. Our survival in general in case of breast cancer is lower compared to western countries and in case of HER2-positive cancers use of 1 year trastuzumab was limited by cost-related issues. Short-course trastuzumab similar to FinHer schedule combined with standard adjuvant chemotherapy remains a feasible option in this patient subgroup. However, data on adjuvant trastuzumab from India are scanty. A small prospective study of 21 patients showed it is a useful strategy with 15 patients being alive at a median follow-up of 42 months.[9]


  Materials and Methods Top


This is a retrospective analysis. Case records of all patients who received adjuvant trastuzumab as 9 weeks' schedule from 2013 January to December 2016 were reviewed. Baseline characteristics, disease-related factors, treatment details, and toxicities will be analyzed. In our institute, all patients with HER2-positive breast cancer after MRM or BCS will receive adjuvant chemotherapy (4X AC followed by 12X weekly Paclitaxel). Along with ER/PR studies, IHC for HER2 neu is also part of IHC. HER2 positivity is established by either IHC 3+ or FISH (done if IHC is 2+). All HER2-positive patients will be offered 1 year of trastuzumab will be offered. Those who cannot afford the standard treatment, 9 weeks of trastuzumab will be given. Trastuzumab will be started after 4 cycles of AC chemotherapy (4 mg/kg loading dose followed by 2 mg/kg weekly). Baseline echocardiogram will be done for all the patients. Patients will be monitored regularly for toxicity. After completion of 9 weeks of trastuzumab, they will continue to receive the remaining chemotherapy and radiation or hormones depending on the stage and receptor status.

Aims and objectives

The objective of the study is to study the toxicity and outcomes of adjuvant short-course trastuzumab in patients with breast cancer.

Inclusion criteria

All patients with HER2-positive breast cancer who received adjuvant 9 weeks' trastuzumab.

Exclusion criteria

Patients with HER2-positive cancers who received neoadjuvant trastuzumab.

Statistical analysis

Survival will be calculated as per Kaplan–Meir analysis. Statistical analysis will be done using SPSS software version 20.0 (SPSS Inc., IBM, Chicago, USA).


  References Top


  1. Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant trastuzumab: A milestone in the treatment of HER-2-positive early breast cancer. Oncologist 2006;11 Suppl 1:4-12.
  2. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013.
  3. 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.
  4. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet 2013;382:1021-8.
  5. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-83.
  6. Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: Final results of the FinHer Trial. J Clin Oncol 2009;27:5685-92.
  7. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809-20.
  8. Tonyali O, Coskun U, Sener N, Inanc M, Akman T, Oksuzoglu B, et al. Nine-week trastuzumab treatment versus 52-week trastuzumab treatment for HER2-positive early-stage breast cancer. J Cancer Res Clin Oncol 2012;138:2145-51.
  9. Hingmire SS, Sambhus MB, Kelkar DS, Joshi S, Parikh PM, Bharath R. Efficacy and safety of short course adjuvant trastuzumab combination chemotherapy in breast cancer. South Asian J Cancer 2017;6:47-50.




 
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