The Hedgehog pathway (HhP) plays an important role in normal embryonic development and its abnormal function has been linked to a variety of neoplasms. Recently, the complex mechanisms involved in this pathway have been deciphered and the cross talks with other important pathways involved in carcinogenesis have been characterized. This knowledge has led to the development of targeted therapies against key components of HhP, which culminated in the approval of vismodegib for the treatment of advanced basal cell carcinoma in 2012. Since then, other compounds have been developed and evaluated in preclinical and clinical studies with interesting results. Today, several medications against components of the HhP have demonstrated clinical activity as monotherapies and in combination with cytotoxic treatment or other targeted therapies against mitogenic pathways that are linked to the HhP. This review aims to clarify the mechanism of the HhP and the complex crosstalk with others pathways involved in carcinogenesis and to discuss both the evidence associated with the growing number of medications and combined therapies addressing this pathway and future perspectives.

PurposeAs cancer burden has risen worldwide, physicians, patients, and their advocates have become aware that the clinical cancer trial research paradigm is not ubiquitous. Furthermore, the number and characteristics of trials that are registered in low- and middle-income countries (LMICs) compared with that in high-income countries (HICs) are unknown.MethodsWe collected retrospective data on trials for breast, lung, and cervical cancer registered in ClinicalTrials.gov or with the WHO International Clinical Trial Registry Platform between 2010 and 2017. The data were then classified as trials within LMICs or HICs using definitions from the World Bank.ResultsIncluded in these analyses were 6,710 trials, of which 3,164 (47%) were breast cancer trials, 3,283 (49%) were lung cancer trials, and 263 (4%) were cervical cancer trials. There were 1,951 (29%) trials from LMICs and 4,759 (71%) trials from HICs (P < .001). Although the proportion of phase III trials in HICs versus LMICs was similar (18% v 17%; P = .66), the number of phase I trials in LMICs was significantly lower than that of HICs (20% v 2%; P < .001). For several LMICs with the highest mortality-to-incidence ratios for breast, lung, or cervical cancer, there were no cancer trials registered in the registration data bases searched for this work.ConclusionThere are differences in access to cancer clinical trials in LMICs compared with HICs. Several factors, such as excessive cost and a lack of infrastructure and expertise, may explain these differences.

Human papillomavirus vaccine programs run the risk of repeating the problems associated with Papanicolaou testing programs in low‐income and middle‐income countries: an efficient, life‐saving tool that unfortunately is underused for cancer prevention. There is a great need for vigilance in the ongoing implementation of the human papillomavirus vaccine in Latin America.

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Introduction: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC), however limited characterization has been pursued. Methods: Clinicopathologic, genomic, and treatment data were collected for 5172 patients with NSCLC tumors which underwent genomic profiling. ATM immunohistochemistry (IHC) was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATMMUT NSCLC was significantly associated with female sex (P=0.02), ever smoking status (P&lt;0.001), non-squamous histology (P=0.004) and higher tumor mutational burden (DFCI: P&lt;0.0001; MSK: P&lt;0.0001) compared to ATMWT cases. Among 3687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q&lt;0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs 28.6%, P&lt;0.0001) compared to tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N=1522) and chemo-immunotherapy (N=951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusion: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

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BackgroundAlthough 1st-line PD-1 monotherapy has improved survival in patients with advanced NSCLC and a PD-L1 TPS ≥50%, responses occur in ~45% of patients. We have previously shown that among patients with NSCLC and PD-L1 expression of ≥50% treated with 1st-line pembrolizumab, clinical outcomes are significantly improved in those with a PD-L1 TPS of ≥90%.1 Here, we report the 3-year follow-up outcomes to 1st-line pembrolizumab in patients with a PD-L1 TPS ≥90% vs <50–89%, and genomic differences between these groups.MethodsPatients with stage IV EGFR/ALK wild type NSCLC and PD-L1 TPS ≥50% who received 1st-line pembrolizumab monotherapy at Dana-Farber Cancer Institute were included. Comprehensive tumor genomic profiling was performed to examine genomic correlates of a very high PD-L1 expression on an expanded cohort of NSCLC samples.ResultsAmong 150 patients included, median age was 69 (range: 46–92), 55.3% were women, 91.9% were current smokers, and 34.0% had a KRAS mutation. At a median follow-up of 38.5 months, median progression-free (mPFS) and overall survival (mOS) in the entire cohort were 4.8 months, and 20.0 months, respectively. When compared to patients with a PD-L1 expression of 50–89% (N=81), those with PD-L1 TPS ≥90% (N=69) had a significantly longer mPFS (6.0 vs 3.9 months, HR 0.66, P=0.02), and longer mOS (27.0 vs 14.6 months, HR 0.63, P=0.03; figure 1). Kaplan-Meier estimates of the 3-year PFS and OS were 23.0% and 43.2% in the PD-L1 TPS ≥90% groups, and 8.6% and 24.0% in the PD-L1 TPS 50–89% group, respectively. A PD-L1 TPS ≥90% was confirmed to be an independent predictor of improved PFS (HR 0.58, P=0.02) and OS (HR 0.57, P=0.01) at multivariable analysis. Patients whose tumors had a PD-L1 TPS ≥90% were also significantly more likely to complete 35 cycles of therapy compared to those with PD-L1 TPS of 50–89% (17.4% vs 3.7%, P<0.01, figure 2). Tumor genomic profiling from 500 NSCLC samples revealed that mutations in STK11, KEAP1, FBXW7, and CTNNB1, which have been previously correlated with immunotherapy resistance, were significantly enriched tumors with a PD-L1 TPS of 50–89% compared to those with a PD-L1 TPS ≥90% (figure 3).Abstract 312 Figure 1(A) Progression-free and (B) overall survival to 1st line pembrolizumab among patients with PD-L1 TPS ≥90% vs 50–89%, at a 3-year follow-up.Abstract 312 Figure 2Barplot showing the percentage of patients who completed 35 cycles of pembrolizumab monotherapy in the PD-L1 TPS ≥90% and 50–89% groupsAbstract 312 Figure 3(A) Oncoprint plot showing the top 15 genes mutated in NSCLC with PD-L1 TPS ≥90% and 50–89%. (B) Gene mutation enrichment analysis showing differentially mutated genes between NSCLCs with PD-L1 TPS ≥90% and 50–89%. ** Adjusted P value <0.01; *Adjusted P value <0.05.ConclusionsPembrolizumab monotherapy continues to demonstrate a meaningful long-term survival benefit at a 3-year follow-up in patients with advanced NSCLC and a PD-L1 TPS ≥90% vs 50–89%. NSCLCs with very high PD-L1 TPS have a more favorable genomic profile. These findings have implications for treatment selection and for clinical trial interpretation and design.ReferenceAguilar EJ, Ricciuti B, Gainor JF, et al. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol 2019 October 1;30(10):1653–1659

8514 Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAFV600E, and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P < 0.001), no difference in KRASG12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P < 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P < 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P < 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P < 0.001) and at the tumor-stroma interface (P < 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.