|Ahead of print
Access to HER2-targeted therapy at a tertiary care center in India: An evolution
Nita S Nair1, Sudeep Gupta2, Jaya Ghosh2, Sangeeta Desai3, Vani Parmar1, Tanuja Shet3, Garvit Chitkara1, Shabina Siddique4, Rajendra A Badwe1
1 Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Breast Disease Management Group, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Submission||23-Sep-2019|
|Date of Decision||23-Sep-2019|
|Date of Acceptance||09-Apr-2020|
|Date of Web Publication||21-Mar-2021|
Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: In a previous retrospective audit from our institution we reported that patients had limited access to HER2-targeted therapy due to financial constraints. Subsequently, the advent of biosimilar versions of trastuzumab and philanthropic support has potentially changed this situation. Herein, we reanalyzed and reported access to HER2-targeted therapy in a more recent cohort of patients.
Methods: Medical records of new breast cancer patients registered in one calendar year were retrospectively reviewed, supplemented by online pharmacy data to extract information on receptor status, use of HER2-targeted therapy, and other relevant variables. Since not all HER2 immunohistochemistry (IHC) 2+ tumors underwent fluorescent in-situ hybridization (FISH) testing, we estimated the probable HER2 amplified from this group based on a FISH amplified fraction in those HER2 2+ tumors who did undergo FISH.
Results: Between January 2016 and December 2016, 4717 new BC patients were registered at our institution, of whom 729 (20.04%) had HER2 IHC 3+ tumors while 641 (17.62%) had HER2 IHC 2+ tumors. The final number of HER2 overexpressing/amplified tumors was estimated to be 928 (729 HER2 IHC 3+, 105 known FISH amplified, and 94 estimated FISH amplified), of whom 831 received treatment at our institution. Overall 474 (57.03%, 95% confidence interval [CI] 53.6–60.4) of these 831 patients received trastuzumab for durations ranging from 12 weeks to 12 months in the (neo)adjuvant setting or other durations in metastatic setting compared to 8.61% (95% CI 6.2–11.6) usage of HER2-targeted therapy in the 2008 cohort.
Conclusion: Access to HER2-targeted therapy has substantially increased among patients treated at a public hospital in the past decade, likely due to the advent of biosimilars, the use of shorter duration adjuvant regimens, and philanthropic support. However, further efforts are required to achieve universal access to this potentially life-saving treatment.
Keywords: Access to care, HER2-targeted therapy, low middle-income countries
Key Message There is increasing access to HER2-targeted therapy among patients with breast cancer because of availability of biosimilars, use of shorter duration adjuvant trastuzumab regimens and funding support for underprivileged patients from several sources.
|How to cite this URL:|
Nair NS, Gupta S, Ghosh J, Desai S, Parmar V, Shet T, Chitkara G, Siddique S, Badwe RA. Access to HER2-targeted therapy at a tertiary care center in India: An evolution. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 29]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=311637
| » Introduction|| |
Breast cancer is the most common cancer among women in India. Although HER2neu overexpression has been a poor prognostic factor, the use of trastuzumab, a HER2-targeted therapy has markedly improved the prognosis of this subgroup. The updated analysis of the HERceptin Adjuvant (HERA) trial showed an absolute benefit of 6% at 11 years of follow-up. Unfortunately, this treatment is expensive and many eligible patients lack access worldwide., Evidence suggests that 1 year of adjuvant trastuzumab is the optimal duration, although lesser durations have also been found to be useful.,,
In a previous retrospective audit from our institution published in 2011, access to HER2-targeted therapy was reported. The estimated number of patients with HER2 overexpressed tumors was 441 (of 2001 new registered patients). Of these, only 38 (8.61%) patients received some form of HER2-targeted therapy, of which 4.54% were in ongoing clinical trials at our institution and 4.08% within routine care. Of note, our institution is a large public sector tertiary cancer center that draws patients from many parts of India and a high proportion (>50%) of patients belong to lower socioeconomic sections of society. The audit evaluated new breast cancer patients registered and treated in 2008.
Three developments occurred in subsequent years that had the potential to impact access to HER2-targeted therapy at our institution. The first was a program supported by the trastuzumab innovator pharmaceutical company that allowed us to provide trastuzumab free of cost (for a 12-week course with taxanes) to a certain number of underprivileged patients being treated at our center, in the (neo)adjuvant setting. This program was subsequently modified to support 1 year of (neo)adjuvant trastuzumab, although in a smaller number of patients, and then subsequently withdrawn. Second, in the past 2 years, a generous philanthropic donor organization started systematically supporting our institution in providing short-course (12-week) (neo)adjuvant trastuzumab to underprivileged patients. Third, biosimilar versions of trastuzumab, which are less expensive, were approved for use in India. The innovator drug price was also brought down in the context of these developments. To evaluate the cumulative impact of these developments on access to trastuzumab, we decided to study access to HER2-targeted therapy in a more recent cohort of breast cancer patients registered at our institution.
| » Methods|| |
We conducted a retrospective audit to evaluate the changed access to HER2-targeted therapy among the cohort of patients registered in our institution in 2016 and compared the outcome with that reported in 2008. We included all patients with histopathologically proven diagnosis of invasive breast cancer, with HER2 immunohistochemistry (IHC) 3+ and those with HER2 amplification on fluorescent in-situ hybridization (FISH), in the treatment access audit. However, not all HER2 IHC 2+ tumors undergo FISH testing at our institution due to financial constraints. Therefore, we estimated the probable number of patients with HER2 amplified tumors from the tumors with HER2 IHC 2+ who did not have FISH testing, based on a FISH amplified fraction in those HER2 2+ tumors who did undergo this procedure. We added this number to patients with IHC 3+ and FISH amplified tumors for calculating access to HER2-targeted therapy.
The details of treatment with HER2-targeted therapy and its duration were accessed from Electronic and paper Medical Record (EMR) and online database of the hospital. The therapeutic decision on the duration of trastuzumab was based on financial considerations.
Data were entered in a previously designed case record form and analyzed in SPSS Version 21.0. The study was approved by the institutional ethics committee.
HER2 testing by IHC and FISH
HER2 IHC was performed using the Ventana 4B5 Pathway antibody prediluted using a Ventana Benchmark XT platform. Score 0 and Score 1 were considered as negative while Score 2 and Score 3 were considered as equivocal and positive, respectively.
HER2 FISH was performed with dual-color fluorescent Abbot Vysis probes on a PathVysion platform using LSI-HER2 spectrum orange and Vysis CEP 17 spectrum green probes. HER2 interpretation by IHC and FISH were done using American Society of Clinical Oncology /College of American Pathologists (ASCO/CAP) guidelines.
Guidelines for reporting HER2/neu status were initially conceived in 2007 by the ASCO/CAP, with revisions in 2013. In IHC, the number of cells showing strong complete membranous staining to qualify for a positive result was decreased from 30% to 10%. Besides, the equivocal was more well-defined >10% tumor cells showing incomplete staining or <10% cells showing complete staining. While this change is thought to potentially increase the number of HER2/neu-positive patients being identified, one study showed that there was a significant increase in tumors classified as equivocal, while there was no increase in positive tumors. In FISH, a category of equivocal was introduced and this meant repeat testing (reflex testing) with another probe.
| » Results|| |
Between 1st January and 31st December 2016, 4717 new breast cancer patients were registered at our institution, of whom tumors from 3636 patients were available for estrogen receptor (ER), progesterone receptor (PR), and HER2 testing by IHC. HER2 3+ expression by IHC was reported in 729 (20.04%) patients and HER2 2+ expression in 641 (17.62%). Of the latter, 338 (52.73%) underwent FISH testing of whom 105 (31.06%) were reported HER2 amplified, 216 (63.90%) non-amplified, and 17 (5.02%) uninterpretable or equivocal. Tumors from the remaining 303 patients were not subjected to FISH testing due to financial constraints. Assuming the same 31.06% amplification rate in these 303 patients, there were potentially 94 more patients with HER2 amplified tumors. The final number of HER2 overexpressing/amplified tumors was estimated to be 928 in the year 2016 (729 HER2 IHC 3+, 105 known FISH amplified, and 94 estimated FISH amplified). Of these 928 patients, 13 were not deemed suitable for HER2-targeted therapy and 84 did not follow-up for further treatment at our institution. The remaining 831 patients were eligible to receive HER2-targeted therapy and were analyzed for access to this treatment.
Overall 474 (57.03%, 95% confidence interval [CI] 53.6–60.4) of these 831 patients received trastuzumab for durations ranging from 12 weeks to 12 months in the (neo)adjuvant setting or other durations in the metastatic setting. This is in contrast to the previously reported 8.61% usage of HER2-targeted therapy in the cohort of patients registered in 2008 [Table 1].
|Table 1: Comparison of 2008 and 2016 registered patients and access to trastuzumab|
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We also analyzed the usage of trastuzumab by stage and the duration of its use in our patients. For this analysis, we included only those patients with documented HER2 IHC 3+ expression (n = 729) or HER2 amplification on FISH (n = 105). From these 834 patients, we subtracted those not suitable for HER2-targeted therapy (n = 13) and those who did not take further treatment at our hospital (n = 84). Thus, the denominator for this analysis is 737 patients. Of these, 185 (25.10%) patients had metastatic breast cancer, of whom 101 (54.6%) received trastuzumab as part of palliative systemic therapy. It is worth noting that philanthropic funding does not support access to HER2-targeted treatment in metastatic patients at our center, so this fraction represents the effect of other variables such as drug cost, health insurance, and socioeconomic condition of our patient population. Only 12 (11.9%) were paid for by the insurance while 89 (88.11%) were self-funded. Of these 101, 16 (15.85%) received the innovator drug and 85 (84.15%) received various available biosimilars.
The remaining 552 patients had nonmetastatic breast cancer, of whom 363 (65.76%) received trastuzumab [Table 2]. Of these, 9 (2.5%) stopped treatment due to toxicity, 169 (46.55%) received trastuzumab for 12 weeks and 185 (50.96%) received it for 12 months. Of the patients who received trastuzumab, 75 (20.67%) received trastuzumab in neoadjuvant setting, 235 (64.74%) in the adjuvant setting, and 53 (14.6%) in both adjuvant and neoadjuvant setting. Of these 363 nonmetastatic cases that received trastuzumab, 55 (15.15%) received the innovator drug and 308 (84.85%) received various available biosimilars. The funding source for these 363 was as follows; 196 (38.5%) were self-funded, 30 (6%) received funding from their insurance, 136 (37.47%) received various philanthropic funding and 1 (0.2%) from additional government schemes.
| » Discussion|| |
Access to effective treatments like trastuzumab is variable in different parts of the world and barriers to access are multifactorial, of which high cost of drug and overall treatment expenses are possibly the most important., Our results suggest increasing access to HER2-targeted therapy in a public sector setting with a predominantly underprivileged patient population. Of note, access has improved in both nonmetastatic and metastatic settings although the numerical improvement is greater in the former group. The possible reasons for the improved access include philanthropic support for treatment and introduction of trastuzumab biosimilars with a reduction of the drug cost. Other factors such as improving per capita income of the Indian population and increasing health insurance coverage could also have contributed to increased access. Although the relative contribution of these factors towards better access cannot be discerned from this analysis, reduction in drug cost is likely to have been the most important contributor based on the results in metastatic patients who were not supported by the philanthropic donation.
The reduction in the cost of the innovator drug itself increased the utilization of the drug. Further reduction in the cost of essential medication like trastuzumab would possibly increase the utilization of this drug (in our data from 8% to 57.03%) and at the same time increasing access to appropriate care, with consequent lives saved. Assuming a patient with weight of 60 kg, the cost of 12 months of innovator drug were approximately 12,00,000–13,00,000 INR or 15600–17000 USD in 2008 and 7,00,000 INR or 9000 USD in 2016, respectively, while the cost of 12-week treatment was 3,50,000 INR or 4500 USD in 2008 and 2,00,000 INR or 2600 USD in 2016, respectively. The cost of biosimilar brand one for 12 months and 12 weeks was 3,50,000 INR or 4500 USD and 90000 INR or 1175 USD, respectively in 2016 and 2019, while the corresponding costs of biosimilar brand two were 3,30,000 INR or 4300 USD and 85,000 INR or 1100 USD, respectively.
This analysis should be considered in the context of the caveat that our definition of access included some patients who received only short-course (neo)adjuvant trastuzumab and could, therefore, be described as less than full access in a proportion of patients. The meta-analysis of shorter duration trastuzumab suggested that shorter durations of trastuzumab may achieve a good balance between efficacy and cardiotoxicity, and serve as a choice for patients with cardiac disease or lower risk of recurrence. Results from many randomized studies suggest that, although shorter courses of trastuzumab have not been proven non-inferior to a 1-year duration, the incremental benefit of the latter (over shorter courses) is small.,, At our institution a large number of patients (46.55%) with the nonmetastatic disease received trastuzumab for 12 weeks.
The outcome results of short-course (neo)adjuvant trastuzumab in our patients are being reported in a separate manuscript but preliminary results have been presented. That study reported 3-year DFS and overall survival of 77.2% and 82.7%, respectively at a median follow-up of 34 months in 103 patients with HER2 receptor-positive breast cancer who received 12 weeks trastuzumab.
| » Conclusion|| |
We suggest that other institutions, especially public hospitals which treat underprivileged patients, make concerted efforts to increase access to potentially curative treatments such as trastuzumab using targeted programs and philanthropic support. Government and pharmaceutical industry initiatives to reduce the cost of treatment are likely to have the greatest impact on access and outcomes.
We gratefully acknowledge VF Brands, India, for its generous philanthropic support towards increasing trastuzumab access in our patients and Women's Cancer Initiative-Tata Memorial Hospital (an NGO) under whose aegis the delivery program was organized.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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