India has witnessed a major paradigm shift in the field of breast cancer and its management over the past 4 decades. The discipline of medical oncology has evolved exponentially over this period—a growth that few other scientific disciplines have experienced. Interventions at the individual, institutional, and health-care delivery levels have significantly contributed to many accomplishments toward comprehensive breast cancer care, despite limited resources. It has been an honor to have contributed to this satisfying, yet incomplete, journey.
Rakesh Chopra, MD
Exploring the Growing Breast Cancer Burden
There is a significant and ever-growing breast cancer burden in India and other low-resource countries. Recently released Global Cancer Observatory 20201 data from India are self-evident, with breast cancer being the most common cancer across genders and age groups. We have an incidence of 178,361 new cases per year, which account for 13.5% of cancer cases in the entire population and 26.3% of cancers in women. Over 26 years, the age-standardized incidence rate of breast cancer in females increased by 39.1% (95% uncertainty interval = 5.1%–85.5%) from 1990 to 2016, with an increase observed in every state of the country.1,2
As per the latest trends, a higher proportion of the disease is being diagnosed among the younger age group in India (median age, 40–50) and the very young age group (median age, 20–35) as compared with the West (median age, > 60).2 The incidence in premenopausal women is increasing, especially in low- and middle-income countries.3
This disparity may be largely attributable to a transition in cancer risk factors, including lifestyle changes. The interplay of various socioeconomic and changing demographic factors that may play major roles in this transition, possibly impacting biology in female Indian patients, includes the following4-6:
- Hereditary predisposition
- Social and cultural influences
- Migration to urban settings
- Sedentary lifestyle
- Increased tobacco usage and alcohol consumption
- Long-term oral contraceptive use and/or hormone replacement therapy
- Lack of breastfeeding
- Delayed childbirth
- Fewer children (average of 2.1 for urban and 3.0 for rural Indian families)
- Deprivation status.
In India, nearly 60% of breast cancer cases are diagnosed at stage III or IV of the disease,6 as compared to 30% in the United States.7
Current Treatment Landscape: Using Safer, More Effective Treatments
Safer and more effective management options have now evolved. We have surely come a long way from the earlier approach of primary upfront mastectomy followed by adjuvant chemotherapy for high-risk breast cancer cohorts to newer neoadjuvant regimens, especially for locally advanced breast cancer, triple-negative breast cancer, and HER2-expressing tumors; these approaches have resulted in a higher proportion of breast-conserving surgeries and oncoplastic procedures at select tertiary care centers. Although novel surgical approaches are now available, the majority of female patients still undergo primary ablative surgical procedures.8 Sentinel node biopsy is not feasible in most places; however, evidence of low axillary sampling has been reported both in upfront and post-neoadjuvant chemotherapy settings, with wide applicability across the subcontinent.9
In hormone receptor–positive disease, the use of gene-expression profiling for prognostication has limited applicability due to excessive financial implications. An indigenous testing panel (Can-Assist) has been developed for risk stratification; it classifies Asian-Indian patients with breast cancer into low risk or high risk of developing distant recurrence at 5 years. This panel could be a relatively cost-effective tool for treatment decision-making in the adjuvant setting. Unfortunately, many women who could otherwise avoid chemotherapy and receive hormone therapy based on risk stratification are being denied this choice.10
With respect to adjuvant chemotherapy regimens, we have made huge strides from the classic Bonadonna cyclophosphamide, methotrexate, and fluorouracil in the 1970s and 1980s and its modifications to anthracycline-based combination chemotherapy protocols in the 1980s and 1990s. With the addition of taxanes and their newer forms in the late 1990s and 2000s, we now understand how to apply these regimens optimally.
Despite these advances, outcomes in triple-negative breast cancer are poor, a problem that we, in India, must grapple with to find answers. Although the majority of women with stage I to III triple-negative breast cancer receive standard neoadjuvant or adjuvant chemotherapy, current studies are evaluating the role of adding platinum compounds. PARP (poly [ADP-ribose] polymerase) inhibitors are also being incorporated in the treatment of patients with BRCA mutant–positive triple-negative breast cancer. Many centers in India have adopted maintenance capecitabine in BRCA-negative cases for 6 months if pathologic complete response is not achieved after neoadjuvant chemotherapy. However, in HER2-positive cases, we are far from adopting neoadjuvant pertuzumab-based combination therapies or adjuvant maintenance T-DM1 (ado-trastuzumab emtansine), for obvious logistical reasons, despite patient assistance programs. A recently launched low-cost T-DM1 biosimilar in India may be a game-changer in this respect.
Radiotherapy offers safer practices, such as intensity-modulated radiation therapy and deep inspiration breath hold, at limited centers. The use of brachytherapy is confined to large tertiary care institutions. Radiation facilities have a minimal presence in rural settings. Due to logistical issues, multiple hospital visits, and the costs thereby incurred, a greater proportion of mastectomies are performed to avoid radiation. Adopting FAST-Forward protocols could circumvent these logistical issues in the postoperative setting.
Systemic therapies in the metastatic cohorts have resulted in improved median overall survival, from approximately 1 year previously to now almost 3 years, with newer treatment options coupled with a substantial increase in 5-year overall survival from 10% to about 30%.6
Before the development of HER2-targeted therapy, HER2-positive metastatic breast cancer was associated with the poorest outcomes, with frequent, early relapses and high rates of visceral and central nervous system metastases. Enhanced use of low-cost biosimilars—eg, trastuzumab and lapatinib—has resulted in their wider applicability. T-DM1 usage is also going to increase drastically now with the availability of a low-cost biosimilar. The Indian government’s efforts to bring anti-HER2 drugs under pricing regulations have enhanced access and improved outcomes.
Current treatment options in metastatic triple-negative breast cancer are largely restricted to systemic chemotherapy. This restriction offers a major challenge that Indian oncologists must address and conquer. In the West, however, immunotherapy, PARP inhibitors, and antibody-drug conjugates have shown great promise. We, in India, must explore these options and come up with innovative solutions. Many centers have now adopted routine PD-L1 , BRCA, and homologous recombination deficiency testing in metastatic triple-negative breast cancer. In hormone receptor–positive metastatic breast cancer, CDK4/6 inhibitors, along with hormonal agents, have been largely adopted as first-line choices in high-resource countries. In India, we are debating whether the use of CDK4/6 inhibitors in second or later lines of therapy has an equal overall survival as compared to first-line usage. The entry of novel PI3K inhibitors has also added a new dimension.
Comprehensive genomic profiling and personalized medicine are now also making inroads.11 With low-cost, next-generation sequencing, liquid biopsies, and widely available circulating tumor cell estimations, the future rests on biomarker-specific and receptor-agonist treatments instead of the conventional “one-size-fits-all” dictum. Other novel strategies focused on response-adoptive therapies, gene-expression profiling, and immune infiltration for personalizing treatment are still undergoing clinical trial development, but they may contribute toward improved outcomes going forward.
Overcoming Obstacles to Care
Despite these advances, the key obstacle we must overcome is access to therapy. The way forward in India is to focus on breast cancer awareness, education, and lifestyle modification practices, putting a clamp on tobacco and alcohol to decrease breast cancer incidence, and to improve early-detection rates in a phased manner. We need more breast cancer–specific training for medical and surgical personnel to standardize and perfect disease management in the curative setting to reduce our metastatic load. This will conserve a valuable resource. We must focus on adopting cost-effective management strategies in resource-constrained settings, such as short HER2 regimens, the FAST-Forward radiotherapy protocol, and the European Society for Medical Oncology–Magnitude of Clinical Benefit Scale, to guide treatment selection and decisions.
The present government has taken positive steps in the direction of equitable health-care access and has launched the largest health assurance scheme in the world: the Pradhan Mantri Jan Arogya Yojana program under the Ayushman Bharat initiative. This program aims to provide health insurance coverage of half a million Indian rupees ($6,700 USD) per family per year for secondary and tertiary care hospitalization to more than 107 million low-income and vulnerable families (approximately 500 million beneficiaries), who account for approximately 40% of the Indian population.12-16 This insurance amount is usually sufficient to complete the entire treatment of a patient’s early breast cancer or locally advanced breast cancer in India in most centers.
Of note, collective initiatives are required to seek the representation of Indian and Asian patients in international clinical trials. Not only does the evidence generated become less applicable to us, but it also represents a global disparity in care when our patients do not have access to newer targeted drugs in the metastatic setting, either through trials or compassionate access programs. Equitable distribution in health is a global necessity, and this disparity must be addressed urgently. Thus far, Indians have been following Western nomograms and protocols, although they may not be suitably applicable to our patient population, with diverse ethnic, genomic, and proteomic features. Our patients are denied the newest treatment modalities either by way of exclusion from trials or from compassionate access programs.
Real-time data generated from our relatively young, treatment-naive population could contribute to international scientific endeavors. Numerous publications from Indian oncologists in peer-reviewed journals over the past few years are a testament to this end.
Looking Toward the Future
We are traversing through an interesting era of the breast cancer journey, whereby the tough and uncertain times of the past have been left behind. We work in the present, with a myriad of treatment options available to us. The future now rests on two pillars: one of personalized medicine and the other of innovative, adaptive clinical trial designs and participation, to pave the way for the development of targeted/mutation-specific therapies.
DISCLOSURE: Dr. Chopra, Ms. Yadav, Dr. Agarwala, and Dr. Mehrotra reported no conflicts of interest.
REFERENCES
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Dr. Chopra is a medical oncologist working in multiple organizations in New Delhi and Gurugram. Dr. Yadav is a public health researcher at the Centre for Social Medicine and Community Health, Jawaharlal Nehru University. Dr. Agarwala is a senior consultant in the Department of Medical Oncology and Hematology-Oncology at Narayana Superspeciality Hospital, Howrah & RN Tagore International Institute of Cardiac Sciences, Kolkata, India. Dr. Mehrotra specializes in preventive oncology and is Chief Executive Officer and Program Lead at the India Cancer Research Consortium, Indian Council of Medical Research, New Delhi.
Acknowledgments: The authors gratefully acknowledge input from Jame Abraham, MD; Tariq Mughal, MD; Sudeep Gupta, MD, DM; Raghunadharao Digumarti, MD, DM; Richard R. Love, MD; Alexandru Eniu, MD, PhD; Deborah Collyar; Gagan Saini, MD; and Rudra Acharya, MCH.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views
of ASCO or The ASCO Post.
