Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

[Small cell lung cancer-Established standards and new approaches]. / Kleinzelliges Lungenkarzinom ­ Etablierte Standards und neue Ansätze.

BACKGROUND: Although the treatment and prognosis of many solid tumor types in the metastatic situation could be considerably improved during the last decade, for a long time no significant progress in the treatment of small cell lung cancer (SCLC) could be achieved. OBJECTIVE: The aim of this article is to describe the current treatment standard for SCLC and to discuss potential approaches for further improvement. METHODS: A selective literature search was carried out in PubMed and abstract lists of relevant conferences. RESULTS: Given the recent approval of two immunochemotherapy regimens based on the combination of anti-PD-L1 antibodies with platinum-etoposide, the therapeutic standard in the first line treatment of metastasized SCLC has finally been improved for the first time in three decades; however, the overall survival benefit has been modest with an improvement of just 2-3 months. In advanced lines of treatment no new approaches could so far show improved outcome compared with established chemotherapy protocols, such as topotecan and combinations of anthracycline, cyclophosphamide and vincristine. The slow progress in SCLC compared to non-SCLC, has been attributed to the complex biology, the exceptionally high proliferation rate and rapid development of resistance to chemotherapy. Increasing knowledge on the molecular and immunological principles of SCLC is increasingly opening up novel treatment approaches. CONCLUSION: There has finally been a slow but clinically meaningful progress in the treatment of SCLC. Patients should be included in clinical trials at the latest after second line treatment, in order to accelerate the speed of the expansion of treatment options.

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations.

BACKGROUND: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. METHODS: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. RESULTS: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. CONCLUSION: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.