New options and open issues in the management of unresectable stage III and in early-stage NSCLC: A report from an expert panel of Italian medical and radiation oncologists - INTERACTION group.

IMPORTANCE: After the PACIFIC trial, concurrent chemo-radiotherapy followed by consolidation therapy with durvalumab for 1 year (limited to PD-L1 tumour proportion score ≥ 1% in the EMA region) is the firmly established standard of care treatment for unresectable NSCLC patients. Several relevant questions are emerging with the growing use of this approach, posing novel challenges in clinical practice. Treatment of oncogene-addicted NSCLCs, management of mediastinal disease recurrence after surgery and the optimal management of patients progressing during or after durvalumab are now some of the most clinically relevant issues. OBSERVATIONS: Patients with unresectable NSCLC harbouring EGFR and HER2 mutations or ALK/ROS1/RET /NTRK1,2,3 rearrangements are unresponsive to immunotherapy. Importance of knowing the tumour genotyping (NGS, preferable DNA and RNA) from the earliest stages of NSCLC, also for the possible use of immunotherapy both in the adjuvant and perioperative setting. In case of mediastinal disease recurrence after surgery, re-biopsy is essential to re-determine the histological and biological characteristics of the disease and the distinction of recurrence in curable and non-curable disease is of pivotal important for the optimal management of subsequent treatments. CONCLUSIONS AND RELEVANCE: Treatment of stage III NSCLC has always been controversial and challenging: Multidisciplinary approach is mandatory and defining resectability is a critical issue. Chemo-radiotherapy followed by maintenance Durvalumab is now the standard of treatment. Herein, we provide a comprehensive overview of the key challenges and open questions that we are currently facing in clinical practice, in unresectable stage III and in early-stage NSCLC, identifying the knowledge gaps and the possible solutions.

miR-17-92a-1 cluster host gene (MIR17HG) evaluation and response to neoadjuvant chemoradiotherapy in rectal cancer.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the gold standard for the treatment of patients with locally advanced rectal cancer (LARC). However, response is variable, and no predictive markers have been validated. The amplification of 13q31-34 seemed to distinguish between nonresponders and responders to NCRT. The miR-17-92a-1 cluster host gene (MIR17HG), which is involved in the development, progression, and aggressiveness of colorectal cancer, and the ABCC4 gene, an ATP-binding cassette transporter, are located at this region. Moreover, the transcription factor c-Myc is closely related to MIR17HG. The aim of this study was to examine the role of MIR17HG, ABCC4, and CMYC gene copy numbers (CNs) in determining response to NCRT. We analyzed DNA CN of pretherapy biopsies from 108 LARC patients and the expression of microRNA (miR)-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1 in 34 biopsies. MIR17HG, CMYC, and ABCC4 gene CNs were frequently altered in pretreatment tumors, amplification being the most frequent alteration. With regard to response to therapy, 41% of responders showed MIR17HG deletion, while MIR17HG amplification was observed in 41% of nonresponders. With regard to pathological T stage (ypT), a higher percentage of ypT3-4 than ypT0-2 tumors showed MIR17HG amplification. Finally, a higher, albeit nonsignificant, variability in the expression of MIR17HG cluster members was detected in nonresponders compared to responders. No association was observed between clinical pathological parameters and ABCC4 or CMYC CN. Our data did not highlight a significant association between MIR17HG, CMYC, and ABCC4 gene CNs and response to NCRT in LARC. However, MIR17HG gene amplification would seem to be related to a lack of response. Evaluation of the expression of MIR17HG cluster members is warranted in a larger case series, together with functional studies, to evaluate the potential of this gene as a new predictive marker.

Genomic alterations in rectal tumors and response to neoadjuvant chemoradiotherapy: an exploratory study.

BACKGROUND: Neoadjuvant chemoradiotherapy is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. METHODS: Forty-eight candidates for neoadjuvant chemoradiotherapy were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade. RESULTS: Both Hidden Markov Model and Smoothing approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 3q29, 7p22-21, 7q21, 7q36, 8q23-24, 10p14-13, 13q12, 13q31-34, 16p13, 17p13-12 and 18q23 chromosomal regions. CONCLUSIONS: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information on response to neoadjuvant chemoradiotherapy and could help to optimize therapy in rectal cancer patients.The data discussed in this study are available on the NCBI Gene Expression Omnibus [GEO: GSE25885].