Real-World Data on Treatment Outcome of ALK-Positive Non-Small Cell Lung Cancer from an Indian Multicentric Cancer Registry.

Lalatendu Moharana The Anaplastic lymphoma kinase inhibitors (ALKi) represent the standard of care for metastatic non-small cell lung cancer (NSCLC) patients with EML4-ALK rearrangements. Various ALKi agents are available; however, not all eligible patients receive treatment with them due to various reasons. Given the limited real-world data available in our country, we aimed to assess treatment outcomes through a multicenter collaboration. This retrospective, multi-institutional study was conducted under the Network of Oncology Clinical Trials India and included a total of 67 ALK-positive metastatic lung cancer patients from 10 institutes across India, with a median follow-up of 23 months. In the first line setting, the objective response rate (ORR) with ALKi was 63.6% (crizotinib: 60.7%, ceritinib: 70%, alectinib: 66.6%, p = 0.508), while with chemotherapy, it was 26.1%. The median progression-free survival (mPFS) for the first line ALKi group was significantly higher than that for chemotherapy (19 vs. 9 months, p = 0.00, hazard ratio [HR] = 0.30, 95% confidence interval [CI]: 0.17-0.54). The mPFS for crizotinib, alectinib, and ceritinib was 17, 22, and 19 months, respectively ( p = 0.48). Patients who received ALKi upfront or after 1 to 3 cycles of chemotherapy or after 4 or more cycles of chemotherapy had mPFS of 16, 22, and 23 months, respectively ( p = 0.47). ALKi showed superior mPFS compared to chemotherapy in the second line (14 vs. 5 months; p = 0.002) and the third line (20 vs. 4 months; p = 0.009). The median overall survival (OS) was significantly better in patients who received ALKi in any line of therapy (44 vs. 14 months, p < 0.001, HR = 0.10, 95% CI: 0.04-0.23). Brain progression was higher among those who did not receive ALKi (69.2 vs. 31.5%). In conclusion, the use of ALKi as first line treatment for ALK-positive metastatic NSCLC patients resulted in improved PFS. PFS and ORR did not significantly differ between patients who received ALKi upfront or after initiating chemotherapy. Notably, patients who received ALKi in second or later lines demonstrated significantly better outcomes compared to those receiving chemotherapy. The use of ALKi in any line of therapy was associated with significantly prolonged OS.

Prognostic Factors and Outcomes of Early-Stage Hodgkin's Lymphoma: Multi-Institutional Data From South India.

Early-stage Hodgkin's lymphoma (ESHL) is highly curable, usually with a combination of chemotherapy and radiation. Real-world data may show differences in survival and prognostic factors when compared to clinical trials. There is limited published literature on ESHL from India. The data on the baseline characters, treatment, and outcomes of patients with ESHL (stage IA, IB, and IIA) were obtained from five institutions' medical records and entered in a common database. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan Meier method, and cox-regression analysis was used to identify prognostic factors. There were 258 patients [median age was 37 (18-75) years; [males:160 (62%); stage I: 41%; B symptoms: 17 (6%); bulky disease:19 (15%)] treated between 2000 and 2020 who were evaluable. The common chemotherapies used were ABVD [N = 180 (70%)], COPP-ABVD hybrid [N = 52 (21%)], and COPP [N = 14 (5%)]. Median number of cycles were 4 (2-8) and 93 (47%) received radiation at end of treatment. After a median follow-up of 60 months, the 5 years EFS was 87% and OS was 92%. On multivariate analysis, the following factors adversely affected the EFS: Male gender [hazard ratio (HR) = 2.23, P = 0.02] and Hemoglobin < 10.5g/dL [hazard ration (HR) = 2.20, P = 0.02], and the following adversely affected the OS: Hemoglobin < 10.5g/dL [hazard ratio (HR) = 4.05, P = 0.001], Male gender [hazard ratio (HR) = 3.59, P = 0.004], Stage 2 [hazard ratio (HR) = 2.65, P = 0.002] and ECOG PS (2-3) [hazard ratio (HR) = 3.35, P = 0.01]. Using the hemoglobin, stage and gender a 3-item prognostic score could identify patients with very good outcomes (score 0; 5 years OS:100%) and poor outcomes (score 3; 5 years OS; 49%). This is one of the first multi-center real-world data exclusively focusing on ESHL from India. Though the survival of the entire population was good, there are subsets of patients who have poor outcomes, which may be identified using simple parameters. These parameters need validation in a larger dataset. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01692-9.

Primary Testicular Mucinous Adenocarcinoma-a Case Report and Review of Literature.

Testicular tumors include germ cell tumors, sex cord stromal tumors, and ovarian type epithelial tumors. Testicular mucinous tumors belong to ovarian type epithelial tumors and are extremely rare with only 31 cases reported in literature so far. Among those, mucinous adenocarcinoma constitutes only 9 cases. There are no standard treatment guidelines owing to their rarity. We report a case of primary testicular mucinous adenocarcinoma managed by orchidectomy, chemotherapy, and retroperitoneal lymph node dissection. A 44-year-old gentleman presented with right testicular tumor with infiltration and ulceration of scrotal skin. Tumor markers were within normal limits. Patient underwent orchidectomy with excision of involved scrotal skin. HPE suggested mucinous adenocarcinoma of testis. Patient was then administered chemotherapy but had progression of disease and hence taken up for retroperitoneal, bilateral pelvic, and bilateral inguinal lymph node dissection with revision of spermatic cord. Patient recovered uneventfully and is on regular follow-up 6 months now since surgery. There are no standard guidelines for the management of mucinous adenocarcinoma of testis. It is essential to rule out mucinous carcinoma of gastrointestinal tract metastasizing to testis before labeling as primary mucinous adenocarcinoma of testis. Surgery remains the mainstay of treatment in metastasis confined to retroperitoneal and inguinal lymph nodes. Further studies are needed to identify optimal chemotherapy regimen for metastatic and adjuvant scenarios.

Homologous recombination DNA repair gene RAD51, XRCC2 & XRCC3 polymorphisms and breast cancer risk in South Indian women.

BACKGROUND: Homologous recombination repair (HRR) accurately repairs the DNA double-strand breaks (DSBs) and is crucial for genome stability. Genetic polymorphisms in crucial HRR pathway genes might affect genome stability and promote tumorigenesis. Up to our knowledge, the present study is the first to investigate the impact of HRR gene polymorphisms on BC development in South Indian women. The present population-based case-control study investigated the association of polymorphisms in three key HRR genes (XRCC2-Arg188His, XRCC3-Thr241Met and RAD51-G135C) with BC risk. MATERIALS AND METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping the HRR variants in 491 BC cases and 493 healthy women. RESULTS: We observed that the XRCC3 Met allele was significantly associated with BC risk [OR:1.27 (95% CI: 1.02-1.60); p = 0.035]. In addition, the homozygous mutant (C/C) genotype of RAD51 G135C variant conferred 2.19 fold elevated risk of BC [OR: 2.19 (95% CI: 1.06-4.54); p = 0.034]. Stratified analysis of HRR variants and BC clinicopathological features revealed that the XRCC3-Thr241Met and RAD51-G135C variants are associated with BC progression. Combined SNP analysis revealed that the individuals with RAD51-C/C, XRCC2-Arg/Arg, and XRCC3-Thr/Thr genotype combination have three-fold increased BC risk. CONCLUSION: The present study imparts additional evidence that genetic variants in crucial HRR pathway genes might play a pivotal role in modulating BC risk in South Indian women.

Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India.

BACKGROUND: The frequency of triple-negative breast cancer (TNBC) incidence varies among different populations suggesting the involvement of genetic components towards TNBC development. Previous studies have reported that BRCA1/2 germline mutations confer a lifetime risk of developing TNBC. However, there is hardly any information regarding the common pathogenic variants (PVs) in BRCA1/2 genes that contribute to TNBC in the Indian population. Hence, we screened for PVs in BRCA1/2 and their association with clinico-pathological features in TNBC patients. METHODS AND RESULTS: The study recruited 59 TNBC patients without hereditary breast and ovarian cancer (HBOC) from South India. The entire BRCA1 and BRCA2 genes were sequenced for the 59 patients using the Illumina HiSeq X Ten sequencer. Among the 59 TNBC genomic DNA samples sequenced, BRCA mutations were identified in 8 patients (13.6%), BRCA1 mutations in 6 patients, and BRCA2 mutations in 2 patients. Among the 6 BRCA1 mutations, three were c.68_69delAG (185delAG) mutation. Remarkably, all the TNBC patients with BRCA mutations exhibited higher-grade tumors (grade 2 or 3). However, among all the BRCA mutation carriers, only one patient with a BRCA2 mutation (p.Glu1879Lys) developed metastasis. CONCLUSION: Our data advocates that South Indian women with higher grade TNBC tumors and without HBOC could be considered for BRCA mutation screening, thereby enabling enhanced decision-making and preventive therapy.

South Asian Declaration-Consensus Guidelines for COVID-19 Vaccination in Cancer Patients.

We provide the South Asian Declaration, containing the consensus guidelines for coronavirus disease 2019 (COVID-19) vaccination in cancer patients.

Impact of xenobiotic-metabolizing gene polymorphisms on breast cancer risk in South Indian women.

BACKGROUND: Functional variants of the xenobiotic-metabolizing genes (XMG) might modulate breast cancer (BC) risk by altering the rate of metabolism and clearance of myriad types of potent carcinogens from the breast tissue. Despite mounting evidence on the role of XMG variants on BC risk, the current knowledge regarding their influence on BC development is still fragmentary. METHODS: The present study examined the candidate genetic variants in CYP1A1, NQO1, GST-T1, GST-M1, and GST-P1 in 1002 subjects (502 BC patients and 500 disease-free women). PCR-RFLP was employed to genotype the mono-nucleotide variation in CYP1A1, NQO1, and GST-P1, and allele-specific PCR was used to detect the deletion polymorphism in GST-T1 and GST-M1 genes. RESULTS: Regarding CYP1A1-M1 polymorphism, the heterozygous TC and mutant CC genotype conferred 1.47-fold (95% CI 1.13-1.91, p = 0.004) and 1.84-fold (95% CI 1.17-2.91, p = 0.009) elevated risk of BC. GST-T1 null genotype was associated with increased BC risk (OR 1.47; 95% CI 1.02-2.11, p = 0.037). For the NQO1 C609T variant, the mutant T allele was associated with BC risk with an odds ratio of 1.22 (95% CI 1.02-1.48, p = 0.034). Combinatorial analysis indicated that the presence of NQO1*2 (CT), CYP1A1-M1 (CC), and GST-P1 rs1695 (AG) genotypes conferred 16.7-fold elevated risk of BC (95% CI 3.65-76.85; p < 0.001). Moreover, GST-M1 null genotype was associated with the development of larger primary breast tumors. CONCLUSION: Xenobiotic-metabolizing gene polymorphisms may play a crucial role in mammary carcinogenesis in South Indian women.

Association of HOTAIR (rs920778 and rs1899663) and NME1 (rs16949649 and rs2302254) gene polymorphisms with breast cancer risk in India.

BACKGROUND: Until now, no study has reported the combined effect of genetic variants of HOTAIR and NME1 towards breast cancer (BC) pathogenesis. Hence, the aim of the present study is to determine the risk of breast cancer development with HOTAIR (rs920778 C > T and rs1899663 G > T) and NME1 (rs16949649 T > C and rs2302254 C > T) genetic polymorphisms in the Indian population for the first time. MATERIALS AND METHODS: To investigate the genetic association of these four SNPs, we conducted a population-based case-control study involving 1011 subjects (502 histologically confirmed BC patients and 509 disease-free controls) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: HOTAIR rs920778 TC genotype elevated the risk of BC (OR = 1.39, 95% CI = 1.06-1.83, p = 0.018) and individuals carrying the mutant allele (T) of rs1899663 had increased BC risk (OR = 1.23, 95% CI = 1.02-1.47, p = 0.026). The presence of the NME1 rs16949649 CC genotype increased the risk of BC (OR = 1.76, 95% CI = 1.15-2.71, p = 0.009). Moreover, the HOTAIR rs920778 variant (TC + CC) increased the risk of BC in pre-menopausal women (OR = 5.86; p < 0.0001). Women carrying 2 or 3 mutant alleles for the investigated SNPs were observed to have an elevated risk of BC. CONCLUSION: The results of the present study highlight the presence of significant associations between NME1 rs16949649 and HOTAIR (rs920778 and rs1899663) polymorphisms and breast cancer development in Indian women.

DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India.

Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell's ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13-2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene-gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

Late recurrence in orbital rhabdomyosarcoma: complete remission after multimodality management.

A case of orbital rhabdomyosarcoma had a localised recurrence 13 years after being treated with chemo radiotherapy. Late recurrences are rare in orbital RMS. Only two cases have been reported to have recurred after five years of follow up. Pathological similarity of both the lesions and occurrence outside the irradiated field excluded a radiation-induced second neoplasm. Immunohistochemistry staining with p 53 was positive. Patient had good response to chemotherapy and radiotherapy. Surgical resection of residue showed complete necrosis. Retreatment with combined modality therapy resulted in complete remission and the patient is on follow up.