ABSTRACT Cancer in older adults is a growing public health concern in India, with approximately 50% of all new cancer cases occurring in individuals aged 60 years and above, according to recent estimates from the Indian Council of Medical Research (ICMR). Older adults often present with a distinct set of medical, psychological, and social vulnerabilities that necessitate tailored approaches to cancer management. The increasing prevalence of solid malignancies among older adults presents substantial challenges for an already overburdened healthcare system. However, oncology care in India lacks a geriatric‐oriented approach, resulting in gaps in both accessibility and quality for older populations. This review provides a detailed exploration of the multidimensional issues of treating older adults with malignancies in India, examining current deficiencies in healthcare delivery, socio‐economic constraints, and potential avenues for enhancing care quality through multidisciplinary collaboration, palliative care integration, and policy reform. The recommendations herein advocate for a model of care that emphasizes holistic support, ensuring dignity, accessibility, and quality outcomes for older adults with cancer in India.
Breast cancer remains the leading cause of cancer related mortality among women globally, yet South Asian populations are critically underrepresented in genomic studies. Here, we present whole-genome and transcriptome analyses of over 500 treatment naive, clinically annotated breast tumors from India, representing the first large scale integrative omics characterization of this population. In addition to established drivers, we identify novel significantly mutated genes, including ISM2, TERF2, and DHRSX, under positive selection, along with previously unreported potentially pathogenic somatic variants. Notably, the distribution of key hotspot mutations appears shaped by immune escape pressures. We uncover recurrent copy number alterations driving lipid metabolic reprogramming (e.g., NCEH1 and PLD1 amplifications) and complex structural events, including IKZF3 promoter hijacking leading to ERBB2 overexpression and TTC28 associated genomic instability findings not previously described in breast cancer. Mutational processes are dominated by DNA repair deficiency, APOBEC activity, and genome instability. We identify three genomic features significantly associated with poor post surgical recurrence free survival. Transcriptomic profiling reveals distinct intrinsic subtypes with divergent immune landscapes, including a high risk HER2 androgenic cluster with the worst outcomes. Additionally, we find a novel transcriptomic signature that robustly captures a HER2 like transcriptional state within triple-negative breast cancer patients with major implications for TNBC treatment. Finally, clinically actionable germline and somatic alterations are revealed with high significance, highlighting opportunities for therapeutic repurposing. Together, the study establishes a comprehensive molecular atlas of breast cancer in an underrepresented population, providing critical insights into tumour biology and advancing precision oncology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge the Council of Scientific and Industrial Research (CSIR), India, for funding the CSIR Indian Breast Cancer Genome Atlas (IBCGA) project (HCP0043). We thank all collaborating institutions and partner hospitals for their continued support. We especially thank all collaborating clinicians for their critical inputs and support staff for their assistance in administering the project across multiple sites. We remain especially grateful to the patients and their families for participating in the project. We also acknowledge the guidance received from the Project Monitoring Committee and CSIR for project management. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was reviewed and approved by the Institutional Ethics Committee of CSIR Institute of Genomics & Integrative Biology (CSIR-IGIB). Ethical approval for patient sample collection and use was obtained from the institutional ethics/review board of all participating hospitals. Patient tumor tissue samples were obtained from institutional biorepositories at the participating centres. Written informed consent had been obtained from all participants at the time of sample collection. All samples and associated clinical data were de-identified prior to analysis. All experiments and procedures were performed in accordance with applicable ethical regulations and guidelines. 1 Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC) RGCIRC/IRB-BHR/41/2022 06/04/2022 2 Saroj Gupta Cancer Centre and Research Institute 25/03/2022/Non-Reg/SB/SR/01 04/05/2022 3 All India Institute of Medical Sciences (AIIMS) IEC/533/17.06.2022, RP-07/2022 17/11/2022 4 Sri Shankara Cancer Hospital and Research Centre SSCHRC/IEC16/123 -Amd 1 21/12/2023 5 Krishna Vishwa Vidyapeeth (KVV) KVV/IEC/01/2025 23/01/2025 6 Balco Medical Centre (VMRF) EC/EXT/06/2024 14/02/2025 7 Indraprastha Apollo Hospitals IAH-BMR-001/01-25 10/04/2025 8 CSIR-Institute of Genomics and Integrative Biology CSIR-IGIB/IHEC/2020-21/02 23/02/2021 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Processed and raw sequencing data from the Indian Breast Cancer Genome Atlas (IBCGA) will be accessible through the IBCGA data portal (https://csir-ibcga.igib.res.in/). The portal provides public access to processed datasets with gene-wise query capabilities and interactive visualisation tools. Raw sequence data are available under controlled access via the same portal. Researchers are required to submit a data access request outlining the proposed research to the Data Management Group. Raw data access is possible following review of the proposal keeping with institutional and regulatory guidelines.
Selection of second-line tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML) is largely guided by kinase domain (KD) mutations in BCR::ABL1; however, a substantial subset of imatinib-resistant cases (~ 40%) lack targetable KD alterations, limiting therapeutic stratification. Given the critical role of the Src homology 2 (SH2) and SH3 domains in regulating BCR::ABL1 activity, we investigated regulatory domain mutations in a cohort of CML with clinically-validated front-line imatinib resistance. Deep sequencing identified a de novo mutation pair, located in SH2 (Y167H) and SH3 (T117P) domain, in 16% cases. Following this, structure-guided molecular dynamics simulations indicated this mutation pair to destabilize the imatinib-compatible BCR::ABL1 conformation, resulting in reduced inhibitor engagement. Likewise, in vitro and in vivo experiments corroborated this non-responsiveness to imatinib. In contrast, computational and experimental analyses identified dasatinib as an effective second-line agent, restoring drug sensitivity despite the regulatory domain perturbations. Case studies further supported the efficacy of dasatinib in overcoming resistance associated with these mutations. Importantly, detection of this mutation pair in an independent validation set underscores the relevance of regulatory domain alterations as a previously under-recognized mechanism of TKI resistance. These findings advocate for routine interrogation of BCR::ABL1 regulatory domains to refine therapeutic decision-making in imatinib-refractory CML.
IntroductionCyclin-dependent kinase 4/6 (CDK4/6) inhibitors, such as Palbociclib and Ribociclib, have significantly improved outcomes for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer. Although clinical trials have established the efficacy of these agents globally, real-world data from India is limited. This study compares the clinical effectiveness and safety profiles of Palbociclib and Ribociclib in a cohort of Indian patients.Materials and methodsThis prospective study included 60 patients with metastatic HR+/HER2- breast cancer treated at Army hospitals and research centers in India between 2020 and 2023. Progression-free survival (PFS), overall survival (OS), and safety profiles were analyzed to assess the real-world performance of Palbociclib and Ribociclib. Patients were treated with either Palbociclib or Ribociclib in combination with standard endocrine therapy.ResultsAmong the 60 patients, the median PFS was 39.40 months for the Palbociclib group and 42.93 months for the Ribociclib group (p = 0.26), indicating no statistically significant difference. The median OS was 41.98 months in the Palbociclib group and 45.51 months in the Ribociclib group (p = 0.15), with Ribociclib showing a slight but non-significant survival advantage. The most common adverse event was neutropenia, which occurred in 26% of patients receiving Palbociclib and 23% of patients on Ribociclib. Deranged liver function tests (LFTs) and fatigue were also reported in both groups.ConclusionsPalbociclib and Ribociclib demonstrated comparable efficacy and safety profiles in this Indian cohort. While no statistically significant differences in PFS or OS were observed, the data suggest a marginal survival benefit with Ribociclib. These findings underscore the importance of individualized treatment plans in HR+/HER2- breast cancer, taking into consideration patient-specific factors. Larger studies with longer follow-up are needed to further clarify the nuances between these two agents.
