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ORIGINAL ARTICLE
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Survival outcomes with 12 weeks of adjuvant or neoadjuvant trastuzumab in breast cancer


1 Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
5 Department of General Medicine, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
6 Department of Radiodiagnosis, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
7 Department of TMC Research Administration Council, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
8 Department of Research Project Manager, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
9 Department of Research Fellow, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission25-Sep-2019
Date of Decision12-Apr-2020
Date of Acceptance25-May-2020
Date of Web Publication27-Jan-2021

Correspondence Address:
Jaya Ghosh,
Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_850_19

PMID: 33753616

  Abstract 


Background: There is limited access to 1 year of adjuvant trastuzumab in resource-constrained settings. Most randomized studies have failed to prove non-inferiority of shorter durations of adjuvant trastuzumab compared to 1 year However, shorter durations are often used when 1 year is not financially viable. We report the outcomes with 12 weeks of trastuzumab administered as part of curative-intent treatment.
Methods: This is a retrospective analysis of patients treated at Tata Memorial Centre, Mumbai, a tertiary care cancer center in India. Patients with human epidermal growth factor receptor (HER2)-positive early or locally advanced breast cancer who received 12 weeks of adjuvant or neoadjuvant trastuzumab with paclitaxel and four cycles of an anthracycline-based regimen in either sequence, through a patient assistance program between January 2011 and December 2012, were analyzed for disease-free survival (DFS), overall survival (OS), and toxicity.
Results: A total of 102 patients were analyzed with a data cutoff in September 2019. The median follow-up was 72 months (range 6–90 months), the median age was 46 (24–65) years, 51 (50%) were postmenopausal, 37 (36%) were hormone receptor-positive, and 61 (60%) had stage-III disease. There were 37 DFS events and 26 had OS events. The 5-year DFS was 66% (95% Confidence Interval [CI] 56–75%) and the OS was 76% (95% CI 67–85%), respectively. Cardiac dysfunction developed in 11 (10.7%) patients.
Conclusion: The use of neoadjuvant or adjuvant 12-week trastuzumab-paclitaxel in sequence with four anthracycline-based regimens resulted in acceptable long-term outcomes in a group of patients, most of whom had advanced-stage nonmetastatic breast cancer.


Keywords: Adjuvant, neoadjuvant, resource constrained, short course, trastuzumab breast
Key Message Twelve weeks of adjuvant or neoadjuvant trastuzumab is a reasonable alternative to one year in resource constrained setting in the management of HER2 positive non-metastatic breast cancer.



How to cite this URL:
Ghosh J, Joy Phillip DS, Ghosh J, Bajpai J, Gulia S, Parmar V, Nair N, Joshi S, Sarin R, Budrukkar AN, Wadasadawala T, Desai SB, Shet T, Patil A, Sawant SP, Dhir AA, Kembhavi S, Popat P, Hawaldar R, Kembhavi Y, Perumal P, Banavali SD, Badwe RA, Gupta S. Survival outcomes with 12 weeks of adjuvant or neoadjuvant trastuzumab in breast cancer. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 22]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=308059





  Introduction Top


Adjuvant trastuzumab has improved disease-free survival (DFS) and overall survival (OS) of patients with human epidermal growth factor receptor (HER2)-positive breast cancer[1],[2] that persists with long-term follow-up.[3],[4] The current standard of care is 1 year of adjuvant trastuzumab.[5] Shorter durations of trastuzumab have also been evaluated in several studies.[6],[7],[8],[9],[10],[11] In the Finland Herceptin (FinHer) study, 9 weeks of adjuvant trastuzumab improved distant DFS compared with no trastuzumab.[6] The randomized studies of shorter duration, 6 months— Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE)[8] and Hellenic Oncology Research Group (HORG)[9] and 9 weeks—short-HER[10] and the Synergism Or Long Duration (SOLD) [11] have failed to prove their non-inferiority compared to 12 months in terms of DFS. However, the absolute differences in DFS between shorter and 1-year trastuzumab arms were small (1–2%) in different studies.[8],[10] In the SHORT-HER study, although the frequentist analysis failed to prove non-inferiority, a pre-planned Bayesian analysis showed a 78% probability that the 9-week trastuzumab arm was non-inferior to 1-year arm.[10] Subgroup analysis of the PHARE study suggested that the additional benefit of 1 year of trastuzumab over 6 months may be questionable in a very low-risk subgroup.[12] In the PERSEPHONE study, however, 6 months was non-inferior to 1 year in early breast cancer.[13] Hence, the debate on trastuzumab duration continues.

There is a lack of access to trastuzumab in several parts of the world because of resource constraints and high cost.[14],[15] In a retrospective study from our institution,[14] it was shown that only 4% of HER2-positive patients could receive trastuzumab as part of routine care, because of financial constraints. Subsequently, a patient support program was initiated at our center that provided access to 12 weeks of trastuzumab to underprivileged patients with non-metastatic disease. The current report presents the survival and other outcomes of consecutive patients enrolled in the initial 2 calendar years of this support program, with sufficient follow-up to draw meaningful conclusions.


  Patients and Methods Top


Design and study population

We undertook a retrospective analysis to evaluate the outcomes in patients who received 12 weeks of adjuvant or neoadjuvant trastuzumab as a part of a patient support program initiated at our institution in January 2011. Consecutive patients enrolled in this program at our institute, Tata Memorial Centre, Mumbai over 2 years between January 2011 and December 2012 were included in the analysis. Data were collected from electronic medical records and patient charts. This analysis was approved by the institutional ethics committee.

Patients had T1-T4, N0-N3, and M0 HER2-positive breast cancer. A few patients had oligometastatic breast cancer defined as less than three sites of metastasis but were being treated with curative intent with planned definitive locoregional treatment. HER2-positivity was defined as either immunohistochemistry (IHC) score of 3+ and/or amplification by fluorescent in-situ hybridization (FISH) using College of American Pathologists (CAP) 2007 criteria.

Treatment

Patients underwent standard locoregional therapy including either breast-conserving surgery (BCS) with axillary lymph node dissection or modified radical mastectomy (MRM). BCS was allowed after neoadjuvant treatment if technically feasible and desired by the patient. Adjuvant radiotherapy in standard doses and schedules was given to all patients undergoing BCS and in those undergoing MRM where the primary tumor size was more than 5 cm and/or four or more axillary lymph nodes were positive for the disease.

Systemic therapy comprised four cycles of anthracycline-based chemotherapy and 12 doses of concurrent weekly paclitaxel (80 mg/m2) with trastuzumab (4 mg/kg loading followed by 2 mg/kg) in the neoadjuvant or adjuvant setting in either sequence (anthracycline followed by taxane-trastuzumab or taxane-trastuzumab followed by anthracycline). Anthracycline regimens included CEF (cyclophosphamide 500 mg/m2, epirubicin 90 mg/m2, 5-Fluorouracil (5-FU) 500 mg/m2), EC (epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2), CAF (cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, 5-FU 500 mg/m2), or AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2). Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive tumors received standard adjuvant endocrine therapy (usually an aromatase inhibitor in postmenopausal and tamoxifen in pre-menopausal patients) for at least 5 years.

Patient evaluation and follow-up

All patients underwent a core biopsy of their tumor to establish diagnosis and receptor status before initiating any treatment. In addition to routine blood and other tests, patients underwent an echocardiogram before the first dose of trastuzumab and before starting anthracycline. Echocardiography was repeated during follow-up if clinically indicated. Patients were clinically followed up once every 6 months for 5 years and yearly thereafter. They also underwent a mammogram once every 12–18 months. They underwent scans for metastatic disease only if indicated by symptoms and/or signs.

Study assessments

The objectives of this analysis were to evaluate DFS, OS, and toxicity in this cohort of patients. DFS was defined as the interval between histopathological diagnosis and the first DFS event. Patients who did not experience a DFS event at the time of data cutoff were censored. DFS events during follow-up included the following: an ipsilateral or contralateral invasive breast cancer, recurrence at any site, a second invasive cancer at any site, or death due to any cause, whichever occurred first. The other endpoints were OS (time interval between histopathological diagnosis and death due to any cause), the pathological complete response rate in those undergoing neoadjuvant therapy (defined as the absence of invasive cancer in the breast and lymph nodes in the surgical specimen), adverse event rate including cardiac and pattern of relapse.

Statistical analysis

DFS and OS were estimated by the Kaplan–Meier method using the SPSS® software (version 22.0; USA).


  Results Top


Patients and treatment

Between January 2011 and December 2012, 104 patients were enrolled in the patient support program; of these, records were available for 102 patients who constitute the study population. HER2 receptor status was confirmed by immunohistochemistry as 3+ score in all except two cases in which it was equivocal and confirmed by amplification on FISH. The baseline characteristics of the patients are shown in [Table 1]. Sixty one (60%) patients had stage-III disease while three had oligometastatic disease with bone involvement. Thirty nine (38.2%) patients underwent BCS.
Table 1: Baseline patient characteristics

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Eighty two (81%) patients received adjuvant trastuzumab and 19 (19%) received it as neoadjuvant therapy. Data on treatment details were missing in one patient. All patients received anthracyclines sequentially except three, two of whom received 12 weeks of paclitaxel and another only adjuvant aromatase inhibitor with 12 weeks of trastuzumab due to multiple comorbidities and age. One patient also received carboplatin with paclitaxel.

All 12 cycles of weekly trastuzumab were completed in 78 patients, 4 patients received 11 cycles, 1 patient received only 7 cycles, 1 patient defaulted after 3 cycles, and details of the number of cycles were not available in 18 patients.

Response, disease-free survival, and overall survival

Three (16%) of the 19 patients who received neoadjuvant paclitaxel-trastuzumab achieved pathological complete response. The median duration of follow-up in surviving patients was 72 months (range 6–90 months). There were 37 DFS events and 26 OS events. A total of 30 patients had relapsed, 19 of whom subsequently died. There were seven deaths in remission, three of which were due to a cardiac cause. Among 30 patients who relapsed 21 (70%) had an only distant relapse, 5 (17%) had only local relapse, and 4 (13%) had both local and distant relapse, as the first site of relapse. Only five (17%) of these 30 patients received any HER2-targeted therapy at relapse. The estimated 5-year DFS [Figure 1] was 66% (95% Confidence Interval [CI] 56–75%) and the OS [Figure 2] was 76% (95% CI 67–85%).
Figure 1: Disease-free survival (DFS) of patients receiving 12 weeks of adjuvant or neoadjuvant trastuzumab

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Figure 2: Overall survival (OS) of patients receiving 12 weeks of adjuvant or neoadjuvant trastuzumab

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Adverse events

13 patients experienced grade 3–4 toxicity during systemic therapy. Febrile neutropenia was seen in 9 out of 86 patients in whom data were available on toxicity during anthracycline-based chemotherapy and in 1 out of 73 patients for whom toxicity data were available during paclitaxel-trastuzumab. Grade III/IV peripheral neuropathy was seen in 3 and grade I/II neuropathy was present in 23 patients out of 65 patients in which neuropathy was documented.

At the time of analysis, 11 (10.7%) of the 102 patients had experienced a cardiac event. Four patients did not recover cardiac function and died, while one patient died even though cardiac function had recovered, the cause of death could not be ascertained in her. In six of these patients, the cardiac event was delayed, occurring after 4 years or later. Two patients had a history suggestive of myocardial infarction, while one patient had ventricular bigeminy. The cardiac event occurred in 2 out of 50 (i.e., 4%) patients who received anthracyclines before paclitaxel and trastuzumab, while it occurred in 8 out of 47 (i.e., 17%) receiving anthracyclines after paclitaxel and trastuzumab. One of the two patients who received paclitaxel and trastuzumab alone also developed a cardiac event. An underlying cardiac disorder in one and higher anthracycline dose in another also contributed to the cardiac toxicity. The details of individual patients with cardiac toxicity are given in [Table 2].
Table 2: Patients with grade-III/IV cardiac toxicity

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  Discussion Top


The present report, which includes 60% locally advanced breast cancer patients, shows a 5-year DFS and OS of 66% and 76%, respectively, using a systemic therapy regimen that included only 12 weeks of trastuzumab. In contrast, the DFS and OS, reported in randomized studies of HERA and the combined National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 and North Central Cancer Treatment Group (NCCTG) N9831 at 4 years, have been in the range of 79–85% and 89–91%, respectively, with the use of 1 year of trastuzumab.[2],[16] However, most patients in these trials had much earlier stages of breast cancer compared to our patient population. It is illustrative to compare our results with subgroup analyses of adjuvant trastuzumab randomized studies. In the updated joint analysis report of NCCTG N9831 and NSABP B-31, the 4-year DFS of patients with tumor size greater than 5 cm was 52% in the control and 78% with 1 year of trastuzumab.[17] In the smaller phase II randomized study E2198 comparing 12 weeks of trastuzumab to 1 year in patients with stage II and IIIA disease, the 5-year DFS and OS were 74% versus 78% and 91% versus 89%, respectively.[18] Though inadequately powered this study did not find a significant difference in the two groups.[18] The other phase-III randomized trials of shorter duration of trastuzumab 6 months or 9 weeks found that it was not non-inferior to 1 year.[8],[9],[10],[11] The PERSEPHONE study demonstrated the non-inferiority of 6 months of trastuzumab compared to 1 year with fewer cardiac toxicity.[13] Thus, although the debate on the optimal duration of adjuvant trastuzumab continues, 1 year remains the standard of care today. The results of this study suggest that a regimen with 12 weeks of trastuzumab improves outcomes compared to historical controls of no trastuzumab, in a real-world setting in relatively advanced stage nonmetastatic patients.

It is interesting to note that one patient who had both hormone receptor and HER-2-positive disease and received only hormone therapy and trastuzumab continued to remain disease-free for 75 months. Though this is just a single patient, the possibility of combining trastuzumab and hormone therapy alone in elderly postmenopausal patients with early stage disease needs to be further studied. There is data using HER targeted therapy and hormone therapy in the metastatic setting[19],[20] and its use in the adjuvant setting needs to be explored.

There was a higher incidence of cardiac toxicity in this study, 11 (10.7%) patients. In studies using 6 months and 9 weeks of adjuvant trastuzumab, the incidence of cardiac dysfunction was 3.4% and 5%, and that of congestive heart failure around 0.5%.[10],[21] Trastuzumab for 1 year resulted in 4% cardiac events in the NSABP B31 study,[22] while in two retrospective analyses in patient cohorts in routine clinical practice, the incidence of symptomatic heart failure was 3% and 6.6%.[23],[24] In this study, 6 of these 11 patients (55%), the cardiac event occurred 4 or more years after treatment completion. The higher incidence in our analysis may be due to higher comorbidity and cardiac predisposition in a routine practice population compared to those accrued in clinical trials. The delayed presentation of cardiac events could reflect delayed detection because of a lack of routine cardiac follow-up after treatment completion. Thus, it suggests that monitoring cardiac function after completion of treatment may enable early detection of cardiac dysfunction. It is also intriguing to note that a cardiac event occurred in only 4% of patients who received anthracyclines before paclitaxel and trastuzumab compared to 17% receiving anthracyclines after it. This is a small retrospective study with many possible confounders, however, the sequence of anthracyclines and paclitaxel-trastuzumab with respect to cardiac toxicity needs to be further evaluated.

This analysis has some limitations, the most important of which is its retrospective nature. The profile of patients included is tilted toward relatively advanced-stage disease. In view of limited access to trastuzumab, there was a selection bias toward younger node-positive patients. Also, because FISH testing was not feasible in many patients, there was a selection bias for patients whose HER-2 status was confirmed as IHC 3+. Then, the relative worth of 12 weeks of trastuzumab versus no trastuzumab or 1 year of trastuzumab cannot be discerned from this analysis. However, in a retrospective audit of breast cancer patients in 2009,[25] the DFS of patients with HER-2-positive patients who did not receive trastuzumab (n = 98, 58 early and 40 locally advanced breast cancer) was 57% (95% CI 46–68%) (unpublished data from our center). Thus, compared to historical controls of those who did not receive any trastuzumab, the use of 12 weeks of trastuzumab appears to improve survival. These are, however, two different retrospective data sets with small sample sizes, wide confidence intervals of point estimates of survival and the data are not directly comparable.


  Conclusion Top


Our results suggest that when standard 1 year of adjuvant trastuzumab is not feasible, a regimen that includes 12 weeks of trastuzumab delivered concurrently with taxanes and sequentially with anthracyclines could be a reasonable alternative.

Acknowledgments

We acknowledge the contribution of Women's Cancer Initiative-Tata Memorial Centre, a nongovernmental organization, which co-ordinated the delivery of short course trastuzumab to our patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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[PUBMED]  [Full text]  


    Figures

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    Tables

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