<div>Abstract<p>Non–small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes <i>EGFR</i>, <i>ERBB2</i>, and <i>MET</i> and fusions involving <i>ALK</i> and <i>RET</i>. In addition to occurring in nonsmokers, alterations in these “nonsmoking-related oncogenes” (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations.</p>Significance:<p>Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic.</p></div>
13 Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB. Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N = 10). All patients received ablative RT (8-50 Gy/1-5 fr) for oligoprogression and/or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools. Results: Median follow-up of the overall cohort was 18 mo; median duration of ICB received in the ICB-RT-ICB arm was 15 mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P <0.01). This clinical phenomenon corresponded to an increased % Ki67 high CD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P <0.01). Deeper immunophenotyping of the Ki67 high subsets revealed associated high expression of GranzymeB and Eomes. Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.
Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.
Thoracic reirradiation for non-small cell lung cancer with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating non-small cell lung cancer with radiation therapy in the setting of prior thoracic irradiation.Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined during 4 rounds on the definition of reirradiation, selection of appropriate patients, pretreatment assessments, planning of radiation therapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents' comments and re-presented in subsequent rounds.Fifteen radiation oncologists participated in the 4 surveys between September 2019 and March 2020. The first 3 rounds had a 100% response rate, and the final round was completed by 93% of participants. Thirty-three out of 77 statements across all rounds achieved consensus. Key recommendations are as follows: (1) appropriate patients should have a good performance status and can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude reirradiation; (2) a full diagnostic workup should be performed in patients with suspected local recurrence and; (3) any reirradiation should be delivered using optimal image guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described.These consensus statements provide practical guidance on appropriate patient selection for reirradiation, appropriate radiation therapy techniques, and cumulative dose constraints.
There is no standard-of-care for recurrent, metastatic nasopharyngeal carcinoma (rmNPC) after first-line chemotherapy. Here, we report the efficacy and safety data of apatinib in rmNPC patients. Thirty-five biopsy-proven rmNPC patients received apatinib at 500 mg/day under a compassionate access programme. Primary end-point was objective response rate (ORR; RECIST v1.1). Kaplan-meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Toxicity was assessed by CTCAE v4.0. 82.9% (29 of 35) of patients had poly-metastatic rmNPC. All patients, except five, were platinum-refractory; 37.1% (13 of 35) received ≥ 2 lines. Median number of apatinib cycles was 4.0 (IQR: 2.0–8.0). ORR was 31.4% (11 of 35 [95% CI: 16.9–49.3]) and disease control rate was 74.3% (26 of 35 [95% CI: 56.7–87.5]); 11 (31.4%) and 4 (11.4%) patients demonstrated response for ≥ 6 and ≥ 12 months, respectively. Median PFS and OS was 3.9 (95% CI: 3.1–5.5) months and 5.8 (95% CI: 4.5–8.0) months, respectively. Among the ≥ 12-month responders, all patients had pre-apatinib EBV DNA titer of <700 (range: 353–622) copies/ml; this was consistent with the association of PFS with pre-apatinib EBV DNA titer (adjusted HR 3.364 [95% CI: 1.428–7.923] for ≥ 4000 copies/ml, P = 0.006). 42.9% (15 of 35) of patients required dose reduction. Nonetheless, only five (14.3%) patients suffered from G3 toxicities (two haematological, one hypertension, one hand-foot syndrome and one elevated aminotransferases). Our data suggests potential efficacy of apatinib in rmNPC patients. Although incidence of severe toxicities was low, dose modification was required in 42.9% of patients.
8530 Background: Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is heterogeneous and L858R derive less benefit from osimertinib than ex19del in both the metastatic and adjuvant setting, which remains poorly understood. We sought to examine the genomic and transcriptomic features of L858R vs ex19del. Methods: Consecutive patients with AJCC7 Stage IA-IIIA EGFR-mutated NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent surgery at National Cancer Centre Singapore were included. Patients who received neoadjuvant therapy were excluded. Fresh frozen tumour and normal samples were subject to whole exome sequencing (WES) at 400X and 100X coverage respectively, with approximately 50 million paired-end reads for RNA-seq per sample. Wilcoxon and Fisher’s exact test were used for association analysis. Results: A total of 203 patients were included. Median age at diagnosis was 66, 66.0% (134/203) were females and 84.2% (171/203) never-smokers. Stage IA comprised 44.3% (90/203), IB 28.6% (58/203), II 15.8% (32/203) and IIIA 11.3% (23/203). Median tumour mutational burden (TMB) was 1.3 mutations/megabase (range 0.3 – 44.3). Ex19del represented 46.3% (94/203) and L858R 41.9% (85/203). Whole genome doubling (WGD) was found in 70.0% (142/203) and was more common in TP53-mutated compared to TP53-wildtype (81.1% vs. 63.6%, p=0.01). TP53 mutations were more common in stage II/IIIA tumours compared with stage IB and IA (50.9% vs 32.8% vs 30.0%, p=0.035). Comparing ex19del and L858R, there was no difference in stage distribution (p=0.337), proportion of TMB≥10 (1.1% vs 5.9%, p=0.103), number of cancer co-driver mutations (p=0.174), TP53 mutations (39.4% vs 32.9%, p=0.437) and WGD (69.1% vs 76.5%, p=0.316). L858R had a higher incidence of smoking mutational signature (median 0.35 vs 0.28, p=0.018) compared to ex19del despite similar smoking history (15.3% vs 12.8%, p=0.67), whereas APOBEC mutational signature was higher in ex19del (median 0.06 vs 0.04, p=0.015). L858R tumors were associated with a higher incidence of co-mutations in RBM10 (21.2% vs 6.38%, p=0.004), RNF213 (10.6% vs 1.06%, p=0.007) and amplification of NTHL1 (15.3% vs 2.13%, p=0.001) and AXIN1 (17.6% vs 3.19%, p=0.002) compared to ex19del. Transcriptomic subtype differed significantly by EGFR mutation with a higher representation of TRU subtype among L858R than ex19del (51.0% vs 35.3%, p=0.010), while GEP score was similar (median 0.189 vs 0.325, p=0.122). Conclusions: L858R have distinct co-mutations and copy number alterations compared to ex19del, in addition to a higher representation of smoking mutational signature and TRU subtype. TP53 co-mutations are more frequently observed in higher stage tumours and are associated with WGD. Our findings highlight the molecular heterogeneity of resected EGFR-mutated NSCLC, which could contribute to the differential outcomes to adjuvant osimertinib between ex19del and L858R.
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