Efficacy Of Platinum-based Chemotherapy Research Articles

Abstract P6-01-09: Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up

Abstract BACKGROUND: In early-stage triple negative breast cancer (TNBC), the addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (CT) increases pathologic complete response (pCR) and relapsed-free survival. However, it is unclear whether CBDCA improves overall survival (OS). In addition, the prognostic and/or predictive role of pathogenic germline variants (PGV) in BRCA1/2 genes and other cancer risk in this setting is not fully understood. Here, we assessed the efficacy of (neo)adjuvant CBDCA and the prognostic and predictive role of a panel of 14 genes in patients (pts) with eTNBC. METHODS: This is a retrospective study on 117 pts diagnosed with early-stage TNBC between 2000-2021 at Hospital Clinic of Barcelona. Eighty-one pts (69%) were candidates for PGV testing. Overall, 14 genes (PGV) (BRCA1, BRCA2, PALB2, BRIP1, CHEK2, TP53, ATM, RAD51C, RAD51D, BARD1, MLH1, MSH2, MSH6 and PMS2) were assessed using the TruSight hereditary cancer panel (Illumina MySeq platform) according to local guidelines. Univariable and multivariable logistic regression and Cox regression analyses were performed to identify clinical and molecular predictors of pCR and relapse-free survival (RFS), respectively. Chi-squared or Fisher’s exact tests were used to assess characteristics’ distribution as appropriate. RESULTS: Of 117 pts, 83 (71%) received CT in the neoadjuvant setting and 28 (24%) in the adjuvant setting. CBDCA was added to standard CT in 68 pts (82%) in the neoadjuvant cohort and 7 pts (6%) in the adjuvant cohort. Among pts with germline testing, 32/81 (39%) harbored PGV. BRCA1 was the most frequently mutated gene (18/32, 56%), followed by BRCA2 (5/32, 16%), PALB2 (4/32, 13%), BRIP1 (2/32, 6%), CHEK2, TP53 and PMS2 (3/32, 6%). Percentages of pts receiving CBDCA were similar between patients with and without PGV (14/16,87% and wild type (53/67,79%)(p=0.120). In the neoadjuvant cohort (n=83), CBDCA was the only variable significantly associated with pCR at both univariate (pCR rates of 58.5% with CBCDA and 14.3% without CBCDA; odds ratio [OR]=8.2 [95% CIs 2.0-55.7], p=0.008) and remained statistically significant after adjusting for PGV, tumor size and nodal status (OR=6.9 [95% CIs 1.4-53.0], p=0.028). pCR rates according to PGV are reported in Table 1. In terms of RFS, addition of CBDCA to neoadjuvant therapy (hazard ratio [HR]=0.2 [0.1-0.45], p< 0.001), PGV (HR=0.2 [0.05-0.9], p=0.048), pCR (HR=0.2 [0.1-0.6], p=0.004) and nodal status (HR=5.1 [1.7-15.2], p< 0.003) were significantly associated with RFS in univariate analyses. In a multivariable model, CBDCA remained an independent predictor of improved RFS along with pCR. When the neoadjuvant and adjuvant cohort were pooled together (n=117), platinum-based CT remained significantly associated with better RFS (HR=0.2 [0.14-0.86], p=0.021) regardless of time of administration (i.e., neoadjuvant or adjuvant). With a median follow-up of 5 years, CBCDA use was not found associated with OS (HR=0.7 [0.3-1.8], p= 0.560). CONCLUSIONS: The addition of CBDCA to standard CT was significantly associated with pCR and RFS but not OS, consistent with the phase III data. The benefit in terms of RFS was independent of the presence and the type of pathogenic germline alterations. Table 1. pCR rates according to PGV Citation Format: Adela Rodríguez Hernández, Benedetta Conte, Laia Fernández, Fara Brasó-Maristany, Belén Pastor, Miriam Potrony, Lorena Moreno, Elia Grau, Joan Antón Puig-Butillé, Aurora Sánchez, Blanca González-Farré, Esther Sanfeliu, Olga Martínez-Sáez, Claudette Falato, Maria Vidal, Nuria Chic, Tomás Pascual, Francesco Schettini, Montserrat Muñoz, Francesc Balaguer, Aleix Prat, Barbara Adamo. Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-09.

Activation of the TGF-β Pathway Enhances the Efficacy of Platinum-Based Chemotherapy in Small Cell Lung Cancer Patients.

Platinum-based chemotherapy is the first choice of treatment for patients diagnosed with small lung cell cancer (SCLC). However, many patients exhibit resistance to it. Therefore, it is imperative to further investigate a prognostic biomarker indicating sensitivity to this therapy. We collected and performed RNA sequencing on 45 SCLC samples from the Zhujiang Hospital (Local-SCLC). In addition, we used a public cohort from George et al. as a validation cohort (George-SCLC). The transforming growth factor β signaling pathway (TGFB) activation status was determined according to the related ssGSEA score. We analyzed immune cell ratios, pathway activation scores, and immune-related genes in SCLC patients to further elucidate the potential mechanisms. A high activation status of the TGFB pathway was associated with improved prognosis in SCLC patients receiving platinum-based chemotherapy (Local-SCLC: HR = 0.0238, (95% CI, 0.13-0.84), p = 0.0238; George-SCLC: HR = 0.0315, (95% CI, 0.28-0.98), p = 0.0315). Immune infiltration analysis showed that the TGFB-HIGH group had more M1 macrophages and Th1 cells, whilst fewer M2 macrophages, Th2 cells, and Treg cells were found in the Local-SCLC cohort. Mechanistic analysis showed that the TGBF-HIGH group was upregulated in STING-mediated immunity, apoptosis, and cell cycle arrest, as well as being downregulated in the process of DNA damage repair. SCLC patients exhibiting a high activation status of the TGFB pathway demonstrate an improved prognosis with platinum-based chemotherapy. The potential underlying mechanism may be related to antitumor immune enhancement and DNA damage repair inhibition.

Next-generation sequencing of homologous recombination genes could predict efficacy of platinum-based chemotherapy in non-small cell lung cancer.

With the widespread use of next-generation sequencing (NGS) in clinical practice, an increasing number of biomarkers that predict a response to anti-tumor therapy in non-small cell lung cancer (NSCLC) has been identified. However, validated biomarkers that can be used to detect a response to platinum-based chemotherapy remain unavailable. Several studies have suggested that homologous recombination deficiency (HRD) may occur in response to platinum-based chemotherapy in ovarian cancer and breast cancer. However, currently there is a lack of proven and reliable HRD markers that can be used to screen for patients who may benefit from platinum-based chemotherapy, especially in NSCLC. NGS was used to screen for gene mutations, including homologous recombination (HR) genes and common driver gene mutations in NSCLC. Cox regression analysis was performed to identify potential clinicopathological or gene mutation factors associated with survival in patients receiving platinum-based chemotherapy, while Kaplan-Meier analysis with the log-rank test was performed to assess the effect of HR gene mutations on progression-free survival (PFS). In a retrospective cohort of 129 patients with advanced NSCLC, 54 who received platinum-based chemotherapy with or without anti-angiogenic therapy were included in the analysis. Univariate and multivariate Cox proportional hazard regression analyses showed that HR gene mutations were associated with platinum-based chemotherapy sensitivity. Efficacy results indicated that the objective response rates (ORR) for patients with BRCA1/2 mutations and BRCA1/2 wild type were 75% and 30.4% (p=0.041), while the median PFS was 7.5 and 5.5 months (hazard ratio [HR], 0.52; 95% CI, 0.27-1.00; p=0.084), respectively. The ORRs of patients with HR gene mutations and HR gene wild type were 60% and 23.6% (p=0.01), and the median PFS was 7.5 and 5.2 months (HR, 0.56; 95% CI, 0.32-0.97; p=0.033), respectively. HR gene mutations show potential as promising biomarkers that may predict sensitivity to platinum-based chemotherapy in advanced and metastatic NSCLC.

PP112 The efficacy of platinum-based chemotherapy and biomarkers in triple-negative breast cancer

PP112 The efficacy of platinum-based chemotherapy and biomarkers in triple-negative breast cancer

DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy and immunotherapy plus platinum-based chemotherapy in advanced non-small cell lung cancer: a retrospective Chinese cohort study

Platinum-based chemotherapy (PC) and immunotherapy plus platinum-based chemotherapy (IPC) remain the first-line treatment for advanced NSCLC. But only a minority patients benefit from PC, and existing biomarkers, such as PD-L1, have been shown to be defective in predicting the efficacy of IPC. Highlighting the need to identify novel biomarkers for the efficacy of PC and IPC. DNA damage repair (DDR) mutations are known to predict response to PC in solid tumors. However, the predictive value of DDR in PC and IPC of NSCLC remains unclear. Patients diagnosed with advanced or metastatic NSCLC were retrospectively included if they underwent next generation sequencing prior to starting treatment. Primary endpoints were to explore whether DDR mutations (DDRmut) are associated with clinical outcomes of PC and IPC. Secondary end point were to explore the association between DDRmut and the choice to add immunotherapy to chemotherapy, and the impact of different DDR pathways on efficacy in PC and IPC. DDRmut showed a strong association with tumor mutation burden-high (TMB-H) versus DDR wild-type (DDRwt) and higher rates of PD-L1 TPS ≥50% positivity. In 63 patients treated with PC, ORRs were 15.38% and 2.86% for DDRmut and DDRwt subgroup (P=0.1536), and DCRs were 88.46% and 45.72% (P=0.00097) at 6 months after PC. The DDRmut patients had significantly improved median PFS (mPFS) and median overall survival (mOS) than DDRwt group (mPFS: 7.6 vs. 3.9 months, HR =1.93, 95% CI: 1.09 to 3.14, P=0.0220. mOS: 29.9 vs. 20.7 months, HR =2.31, 95% CI: 1.09 to 4.9, P=0.0250). Moreover, among 37 patients treated with IPC, ORRs were 45% and 11.76% for DDRmut and DDRwt patients (P=0.0365), and the DCRs were 95% and 70.58% (P=0.0752), respectively at 6 months after IPC. The DDRmut patients had significantly improved mPFS compared to the DDRwt group (19.5 vs. 4.5 months, HR =3.28, 95% CI: 1.53 to 9.56, P=0.0022). In DDRmut group, mPFS of IPC recipients was significantly better than that of PC recipients (19.5 vs. 7.6 months, HR =2.09, 95% CI: 0.98 to 4.42, P=0.050). There is potential for DDR to serve as a positive predictor of PC and IPC in advanced NSCLC patients.

NCALD as a potential predictive biomarker for the efficacy of platinum-based chemotherapy in ovarian cancer.

Aim: Since reliable response predictors to platinum-based chemotherapy in ovarian cancer (OC) are scarce, we characterize NCALD as apredictive biomarker. Materials & methods: NCALD mRNA (n=100) and protein (n=102) expression was analyzed in OC samples and associated with patient outcome. A stable OC cell line knockdown was generated and cellular response to platinum was explored. Results: High NCALD mRNA and protein expression was significantly associated with longer overall patient survival (p=0.037/0.002). Knockdown experiments revealed a significant association between cisplatin sensitivity and NCALD expression. Conclusion: Low NCALD expression was associated with reduced sensitivity to platinum-based chemotherapy. NCALD may be a new biomarker candidate to identify patients who might benefit from platinum-based chemotherapy.

Characteristics of homologous recombination repair pathway genes mutation in ovarian cancers.

Few studies have investigated the characteristics of non-BRCA homologous recombination repair (HRR) pathway somatic mutations, and the impact of these mutations on efficacy of treatment in ovarian cancer patients is not clear. Therefore, we conducted this study to analyze the frequency and spectrum of somatic mutations in HRR pathway genes in patients with ovarian cancer and to examine the relationships between somatic mutations in HRR pathway genes and their effects on the efficacy of platinum-based chemotherapy. We performed targeted sequencing of 688 genes related to the occurrence, development, treatment, and prognosis of solid tumors. Somatic mutations were identified by paired analysis of tumor tissue and germline DNA in blood cells. A total of 38 patients with ovarian cancer were included in the study, and 35 (92.1%) patients were diagnosed with high-grade serous carcinoma. All patients exhibited somatic mutations in the tumor tissue samples. The commonly mutated genes were TP53 (73.7%), BRCA2 (55.3%), NF1 (52.6%), BRCA1 (47.4%), and CDH1 (47.4%). Overall, 71.1% of the patients exhibited mutation in at least one HRR pathway gene. The most frequently altered HRR genes were BRCA2 (55.3%), followed by BRCA1 (47.4%), ATM (44.7%), BARD1 (42.1%), and CHEK1 (36.8%). The median progression-free survival (PFS) in patients with HRR pathway mutation was 36.0 months compared with 13.6 months in patients with no HRR pathway mutation (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08-0.77; p = 0.016). Patients harboring BRCA1/2 and/or CDK12 mutations displayed a longer PFS (median, 36.0 months) compared with patients with no BRCA1/2 or CDK12 mutation (median, 13.6 months; HR, 0.21; 95% CI, 0.07-0.61; p = 0.004). In multivariate analysis Cox proportional hazards models, after adjustment for tumor stage at diagnosis and histology of initial diagnosis, patients with HRR pathway mutation had a longer PFS than patients with HRR wild-type genes (p = 0.006). HRR pathway somatic mutations are common in Chinese patients with ovarian cancer. HRR pathway somatic mutations were associated with improved sensitivity to platinum-based chemotherapy. Large-scale prospective studies are needed to verify our findings.

EP02.01-005 The Efficacy of Platinum-Based Chemotherapy as Adjuvant Therapy in EGFR Mutant Lung Adenocarcinoma

The ADAURA trial reported that osimertinib improved disease-free survival (DFS) compared with placebo as an adjuvant chemotherapy for stage II-IIIA EGFR mutant lung cancer. Currently, platinum-based adjuvant chemotherapy is the standard adjuvant therapy for patients with and without EGFR mutations. This study aimed to evaluate the efficacy of platinum-based adjuvant chemotherapy in stage II-IIIA EGFR mutant lung adenocarcinoma.

Homologous recombination repair gene mutations as a predictive biomarker for immunotherapy in patients with advanced melanoma.

BackgroundNowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) is one of the DNA damage response (DDR) pathways, which has been proved to correlate with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy, and immunotherapy in a variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma.MethodsData of advanced melanoma patients from an independent cohort (Samstein2018) were used to analyze the correlation with immunogenic markers and the prognostic effect of HRR on immunotherapy, and another four cohorts (pooled cohort: Miao2018, Allen 2015, Hugo2016, and Synder2014) were used for validation. Immune infiltration cell scores analyzed by TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment.ResultsCompared to patients with an HRR wild type (HRRwt), those with HRR mutations (HRRmut) in anti-CTLA-4-treated patients of the Samstein2018 cohort had higher tumor mutation burden (TMB; P = 0.0041) and longer median overall survival (mOS; P = 0.0094). In terms of results validation, it was also confirmed that the mOS (P = 0.0014) of HRRmut patients receiving anti-CTLA-4 therapy was significantly better than that of HRRwt patients in the pooled cohort, and objective response rates (ORR; P = 0.0053) were also found to be significant. However, there was no significant difference in mOS between HRRmut patients who received anti-PD-1/L1 therapy and HRRwt patients in either the discovery (Samstein2018 cohort, P = 0.94) or validation (pooled cohort, P = 0.96) set. Exploratory analysis found that although HRRmut patients showed no significant difference in mOS between anti-CTLA-4 and anti-PD-1/L1 therapy (P = 0.79), the mOS value of the anti-CTLA-4 therapy group (31.7 months) in HRRmut patients was numerically superior to the anti-PD-1/L1 therapy group (27.5 months). In contrast, the mOS of the anti-CTLA-4 therapy group was significantly lower than that of the anti-PD-1/L1 therapy group (12.4 vs. 32.0 months) in HRRwt patients. In addition, transcriptome profiling analysis revealed that the 29 (65.9%)-gene mutation of the HRR pathway associated with reshaping of the immunological microenvironment in melanoma.ConclusionsHRR mutations were associated with a higher TMB level, and better anti-CTLA-4 therapy outcomes. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.

Homologous recombination deficiency (HRD) score predicts response to platinum-based chemotherapies in Chinese high grade serous ovarian cancer patients (188)

<b>Objectives:</b> Homologous recombination repair deficiency (HRD), as a major feature of high-grade serous ovarian, is associated with the efficacy of PARP inhibitor (PARPi) therapy. Tumors present with HRD are characterized by a defect in DNA double-strand break repair, which is thought to render particularly sensitive to inter-strand cross-linking agents, including platinum analogs. However, whether HRD status confers sensitivity to platinum-based chemotherapies in high-grade serous ovarian patients remains poorly defined. <b>Methods:</b> In this study, we used the machine learning method to build a genomic scar (GS) model to predict HRD, which takes different types of chromosomal copy numbers into consideration for the calculation of genomic instability. GS score ≥50 was defined as HRD positive, accounting for 94.5% of <i>BRCA</i>-deficient events. HRD score, consisting of heterozygous (LOH), telomeric allelic imbalance (TAI), and Large-scale transition (LST), was also determined (HRD-positive [score ≥42] versus HRD-negative [score <42]), and both GS score and HRD score impacts on clinical efficacy were explored. <b>Results:</b> A total of 94 high-grade serous ovarian patients who received first-line platinum-based chemotherapy but no further PARPi maintenance therapy was picked out and analyzed for the predictive value of GS score and HRD score in platinum-based chemotherapy efficacy. GSS-positive was observed in 78/94 (82.9%) patients, and HRD-positive was observed in 74/94 (78.7%) patients, concordance between GS score and HRD score was 91%. Progression-free survival (PFS) (GSS: HR: 0.604; p=0.00082; HRD: HR: 0.64; p=0.00134), overall survival (OS) (GSS: HR: 0.482; p=0.00155; HRD: HR: 0.496; p=0.00231), and platinum-free interval (PFI) (GSS: HR: 0.621; p=0.00204; HRD: HR: 0.664; p=0.00482) were significantly longer in both GS-positive and HRD-positive groups (Figure 1). In <i>BRCA</i>-wildtype patients, survival differences were also seen in GSS-positive versus GSS-negative (p=0.007674) and HRD-positive versus HRD-negative (p=0.017588) populations (Figure 2). Platinum-resistant patients with a PFI of less than six months show a significantly lower GSS-positive rate and HRD-positive rate than platinum-sensitive patients (PFI>6 months) (Figure 2).Fig. 1 <b>Conclusions:</b> HRD status identifies high-grade serous ovarian patients and remains a significant predictor of response to platinum-based chemotherapy. GSS showed high concordance with the HRD score, which implied the high robustness of the GS model.

Abstract 5395: DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer

Abstract Background: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors. However, their predictive value remained unknown in patients with colorectal cancer. Methods: The genomic and survival datas from the TCGA-COAD and TCGA-READ cohorts of patients receiving platinum-based chemotherapy were used to analyze the predictive value of DDR mutations on platinum-based chemotherapy. Result: The DDR genes were commonly mutated (85.82%) in the TCGA-COAD and TCGA-READ cohorts. The objective response rates (ORRs) were 80% for the patients with DDR mutations (DDRmut) subgroup and 56% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the disease control rates (DCRs) were 86% for the DDRmut subgroup and 56% for the DDRwt subgroup (P&amp;lt;0.05). In patients with stage I, II and III colorectal cancer, there was no significant difference in the overall survival (OS) between DDRmut subgroup and DDRwt subgroup (Hazard Ratio=0.48, 95%CI 0.1−2.31, log-rank P=0.35). In patients with stage IV colorectal cancer, the OS was significantly better among the DDRmut patients than in the DDRwt subgroup (Hazard Ratio=0.21, 95%CI 0.06−0.8, P= 0.011). Conclusions: DDR mutations may serve as a positive predictor of platinum-based chemotherapy therapy in patients with CRC and their clinical value warrants further investigation. Citation Format: Yan Lin, Jinyan Zhang, Xiaoli Liao, Yumei Zhang, Min Luo, Qian Li, Mingzhi Xie, Chaoyong Liang, Sina Liao, Yating Zheng, Xue Hu, Mengli Huang, Rong Liang, Yongqiang Li. DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5395.

Correlation between homologous recombination repair gene mutation and immunotherapy efficacy in patients with advanced melanoma.

e21551 Background: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) was a pathway of the DNA damage response (DDR), has been shown to be associated with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy and immunotherapy in variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. Methods: An independent cohort (Samstein2018) with data from 99 patients with advanced melanoma were used to analyze the correlation with immunogenic marker the prognostic effect of HRR on immunotherapy, and another four cohorts (Miao2018, Allen 2015, Hugo2016, and Synder2014) are used for validation. Immune filtration cells scores analyzed by the TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. Results: Compared to patients with HRR pathway wild-type (HRRwt), those with HRR mutations (HRRmut) in an independent anti-CTLA-4-treated cohort had higher tumor mutation burden (TMB; median: 29.55Muts/Mb versus 4.46Muts/Mb; P = 0.0003), objective response rates (ORR; P = 0.007), and longer overall survival (OS; median: 58 versus 22 months, hazard ratio (HR) = 2.4, 95%CI 1.17-4.92, P = 0.014). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the ORR and OS. However, there was no correlation between HRRmut and OS in the anti-PD-1-treated cohort. Subgroup analysis showed that although patients with HRRmut received the same benefits from anti-CTLA-4 and anti-PD-1/L1 therapy (p = 0.59), the value of anti-CTLA-4 therapy in the HRRmut group was similar or even better than that in the anti-PD-1/L1 therapy group (24.1 months vs 22.7 months), which unlike it in the HRRwt group (10.8 months vs 32.0 months). In addition, transcriptome profiling analysis revealed that 44 (66.7%) genes mutation of HRR pathway associated with reshaping of the immunological microenvironment in melanoma tumors. Conclusions: HRRmut were associated with a higher TMB level, and immunotherapeutic effect. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.

Efficacy of platinum-based chemotherapy in metastatic breast cancer and HRD biomarkers: utility of exome sequencing

Metastatic breast cancer (MBC) is frequently managed by platinum-based chemotherapy during the disease course. The real benefit of these treatments is uncertain at advanced stages of the disease and in non-triple-negative subtypes. Since homologous recombination deficiency (HRD) could inform about tumor sensitivity to DNA-damaging agents, we aimed to determine biomarkers of genomic instability, and their link with platinum efficacy. In this single-center study, we report BRCA1/2 mutational status, HRD score and signature 3 levels, all obtained by tumor exome sequencing, in 86 patients with various subtypes of MBC and who received platinum-based chemotherapy. Overall response rate, disease control rate, PFS and PFS2/PFS1 ratio were evaluated to assess platinum-based chemotherapy efficacy. Among the 86 tumor samples analyzed, 7 harbored BRCA1/2 mutations. We found a subset of BRCA-proficient MBC with high HRD score or high S3 levels, comparable to BRCA-mutated tumors. However, these patients with high HRD score or high S3 tumor level do not seem to benefit more from platinum-based chemotherapy than the others, in terms of response rates and/or PFS, regardless of BC molecular subtype. By multivariate analysis, only the absence of liver metastases was independently associated with significantly better PFS on platinum-based chemotherapy. However, some of our exploratory analyses reveal that certain methods, when optimized, seem to associate with platinum benefit. Tumor exome sequencing methodology for quantifying HRD has to be approached systematically, and further validated and standardized prior to its clinical use. Further studies are warranted to confirm these results to guide platinum use in MBC.

Investigation of PALB2 Mutation and Correlation With Immunotherapy Biomarker in Chinese Non-Small Cell Lung Cancer Patients.

BackgroundPALB2, a gene in the homologous recombination repair (HRR) pathway of the DNA damage response (DDR), is associated with the efficacy of platinum-based chemotherapy, immunotherapy, and PARP inhibitor therapy in several tumors. However, the PALB2 characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown.MethodsTumor tissue samples from advanced Chinese NSCLC patients were analyzed by next-generation sequencing (NGS) (panel on 381/733-gene). Tumor mutation burden (TMB) is defined as the total number of somatic non-synonymous mutations in the coding region. Microsatellite instability (MSI) was evaluated by NGS of 500 known MSI loci. Programmed Cell Death-Ligand 1 (PD-L1) expression was evaluated using immunohistochemistry (Dako 22C3 or SP263). One independent cohort (Rizvi2018.NSCLC.240.NGS cohort) containing genomic and clinical data from 240 patients with advanced NSCLC and two cohorts (the OAK and POPLAR study cohort) containing genomic and clinical data from 429 patients with advanced NSCLC were used to analyze the prognostic effect of PALB2 on immunotherapy.ResultsGenetic mutation of 5,227 NSCLC patients were analyzed using NGS, of which 162 (3.1%) harbored germline PALB2 mutation (PALB2gmut) and 87 (1.66%) harbored somatic PALB2 mutation (PALB2smut). In NSCLC patients with PALB2gmut and PALB2smut, the most frequently mutated gene was TP53 (65%, 64%). PALB2smut (14.52 Muts/Mb) was associated with higher TMB (p < 0.001) than PALB wild-type (PALB2wt) (6.15 Muts/Mb). However, there was no significant difference in TMB between PALB2gmut (6.45 Muts/Mb) and PALB2wt (6.15 Muts/Mb) (p = 0.64). There was no difference in PD-L1 expression among PALB2gmut, PALB2smut, and PALB2wt. In the Rizvi2018.NSCLC.240.NGS cohort, there was no difference in progression-free survival (PFS) (HR =1.06, p = 0.93) between PALB2 mutation (3.15 months) and PALB2wt (3.17 months). The OAK and POPLAR study cohort of NSCLC patients showed that there was no difference in overall survival (OS) (HR =1.1, p = 0.75) between PALB2 mutation (10.38 months) and PALB2wt (11.07 months).ConclusionsThese findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.

Efficacy of Chemotherapy versus Transcatheter Arterial Chemoembolization in Patients with Advanced Primary Hepatic Neuroendocrine Carcinoma and an Analysis of the Prognostic Factors: A Retrospective Study.

BackgroundPrimary hepatic neuroendocrine carcinoma (PHNEC) is a rare liver tumor, and there is no clear therapeutic recommendation for patients with advanced PHNEC. This study aims to compare the efficacy of platinum-based chemotherapy (etoposide combined with cisplatin/carboplatin, EP/EC) and transcatheter arterial chemoembolization (TACE) in patients with advanced PHNEC, and to evaluate the relevant prognostic factors.Patients and MethodsThe clinical data of 41 patients with advanced PHNEC from June 2014 to October 2019 were retrospectively reviewed.ResultsAt a median follow-up time of 13.9 months, the median overall survival (OS) was 14.8 months in the EP/EC group and 12.2 months in the TACE group (P = 0.040). The median progression-free survival (PFS) was 4.4 months and 2.7 months in the EP/EC group and the TACE group, respectively (P = 0.005). No significant differences in the overall response rate and disease control rate were observed between the EP/EC group and the TACE group (26.1% vs 11.1%, P = 0.429; 73.9% vs 44.4%, P = 0.055, respectively). A univariate analysis indicated that the Eastern Cooperative Oncology Group performance status (ECOG PS), Ki-67, tumor number, and treatment options were prognostic factors for OS. A multivariate analysis further showed that ECOG PS (P < 0.001), Ki-67 (P = 0.003), and treatment options (P = 0.022) were independent prognostic factors for OS.ConclusionKi-67, ECOG PS, and treatment options were the independent prognostic factors for OS in patients with advanced PHNEC. EP/EC may be a better choice for patients with advanced PHNEC.

EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy

IntroductionIn classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described. Study DesignA retrospective, single-center, case series MethodsPatients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method. ResultsAmong 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N = 17, 94%) and second-line settings (N = 1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 – NR). ConclusionsThe efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.

Abstract 374: NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC

Abstract Background: In the era of precision medicine, better response of anti-tumor therapies attribute to detection of specific molecular markers. However, up to the present no validated biomarker for platinum-based chemotherapy could be used in clinic. Next-generation sequencing (NGS) technology has been applied for non-small cell lung cancer (NSCLC) molecular typing for years. Whether analysis of homologous recombination (HR) gene mutations based on NGS results could predict the efficiency of platinum-based therapy in NSCLC is still obscure. Methods: NGS has been performed for screening homologous recombination (HR) gene mutations, as well as common driver genes in NSCLC, with tumor samples. Advanced or metastatic NSCLC patients receiving platinum-based chemotherapy were included for efficacy analysis. Results: 129 patients with HR genes information were included for analysis. Among the 129 patients, 55 patients were received platinum-based chemotherapy. The efficiency results showed the objective response rates (ORR) of patients with BRCA1/2 and without BRCA1/2 mutations were 71.4% and 31.3%; and the median progression free survival (PFS) were 7.5 and 5.6 months(p=0.161), respectively. The ORR of patients with and without HR genes mutations were 57.9% and 25.0%; and the median PFS were 8.0 and 5.3 months (p=0.039), respectively. Conclusions: NGS based profiling of BRCA1/2 and other gene mutations in HR pathways have a promising predictive value for efficacy of platinum-based chemotherapy in advance and metastatic NSCLC. Citation Format: Linlin Zhang, Xin Wang, Hui Song, Fanlu Meng, Guowei Yu, Diansheng Zhong. NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 374.

Efficacy of platinum-based chemotherapy in advanced triple-negative breast cancer in association with homologous recombination deficiency.

e13051 Background: Previous studies have identified that at least 50% of triple negative breast cancer (TNBC) harbor mutation characteristics of homologous recombination deficiency (HRD). Thus, more sophisticated research into comprehensive genomic profiling of HRD is urgently needed. Whereas BRCA1/2-deficient advanced TNBC patients are sensitive to treatment with platinum, it is not yet clear whether HRD status could predict platinum response. Methods: 3DMed-HRD algorithm was developed based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) as previously described. HRD status was defined as HRD positive (deleterious mutation in BRCA1/2 or HRD score ≥30) or HRD negative (no deleterious mutation in BRCA1/2 and HRD score &lt; 30). Tumor samples from 207 TNBC patients were analyzed by next-generation sequencing. Deleterious or suspected deleterious mutations were included for analysis. Among the overall cohort, 34 patients with advanced TNBC treated with chemotherapy were analyzed. Cox regression model was applied to evaluate the relationship between HRD status and clinical outcomes. Results: Deleterious BRCA1/2 mutations were detected in 22.2% (46/207) of TNBC patients as well as 54.6% (113/207) were defined as HRD positive. The most frequent mutations in HRD-positive patients were TP53 (93.5%), MYC (29.0%), PIK3R1 (22.6%), PTEN (22.6%) and MCL1 (19.4%), while TP53 (77.8%), MYC (29.6%), PIK3CA (18.5%), KMT2C (14.8%) and RIT1 (14.8%) enriched in HRD-negative patients. Mutations in DNA Damage Response (DDR), P53, Checkpoint and Receptor Tyrosine Kinase (RTK) pathways were most involved in HRD positive patients. In advanced TNBC cohort, 19 patients received platinum-based and 15 received platinum-free chemotherapy in the first-line treatment. The progression-free survival (PFS) of the platinum-based group was longer than that of the platinum-free group (media PFS 9.1 vs 2.2 months, HR 0.44, 95%CI, 0.20-0.94, P = 0.009). In HRD-positive patients, median PFS was significantly longer in platinum-based group (N = 6) than platinum-free group (N = 8) (media PFS 13.6 vs 1.9 months, HR 0.30, 95%CI, 0.09-0.95, P = 0.008). No significant difference in PFS between platinum-based and platinum-free group (p = 0.332) in patients with HRD-negative tumors. Patients with mutations in homologous recombination (HR) pathway had a worse PFS compared to wild-type in platinum-free group (1.4 vs 3.0 months, p = 0.050). Conclusions: Our findings illustrate the potential of HRD status as a marker to guide chemotherapy in advanced TNBC. In HRD positive patients, platinum-based chemotherapy might be a preferable regimen. Patients with mutations in HR pathway had a shorter PFS in platinum-free group. Prospective study with a larger sample-size is needed for further validation of our findings.

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

In vitro and in vivo analysis of metabolites involved in the TCA cycle and glutamine metabolism associated with cisplatin resistance in human lung cancer

ABSTRACT Elucidating the dysregulated metabolic pathways in cancer cells and their relevance to cisplatin resistance could yield new insights into cancer therapy. We previously reported that eight metabolites involved in the tricarboxylic acid (TCA) cycle and glutamine metabolism were associated with platinum-based chemotherapy efficacy in human lung cancer. Here, we investigated the metabolic differences upon cisplatin treatment in lung cancer in vitro and in vivo. A simple and partially validated standard addition method was applied for the quantification of five metabolites involved in the TCA cycle and glutamine metabolism using amide hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). The present study investigated the levels of these biomarkers in A549 cells and the cisplatin-resistant A549-DDP cells, as well as in the plasma before and after cisplatin treatment in A549 xenograft mice. Levels of five metabolites, including 2-hydroxyglutaric acid (2-HG), α-ketoglutarate (α-KG), succinate, glutamine, and glutamate, showed a decreasing trend in A549-DDP cells. In addition, 2-HG and glutamine were the most significantly altered metabolites in cisplatin-treated A549 xenograft mice. These data indicate that the TCA cycle and glutamine metabolism play important roles in cisplatin-based chemotherapy resistance in lung cancer. Our results provide a new angle for exploring the molecular mechanisms underlying cisplatin resistance.