Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria-as defined largely based on early-stage carcinoids-in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at  metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive malignancy, which was recently found to comprise three major genomic subsets: small cell carcinoma-like, non-small cell carcinoma (predominantly adenocarcinoma)-like, and carcinoid-like. To further characterize adenocarcinoma-like subset, here we analyzed the expression of exocrine marker napsin A, along with TTF-1, in a large series of LCNECs (n=112), and performed detailed clinicopathologic and genomic analysis of napsin A-positive cases. For comparison, we analyzed napsin A expression in other lung neuroendocrine neoplasms (177 carcinoids, 37 small cell carcinomas) and 60 lung adenocarcinomas. We found that napsin A was expressed in 15% of LCNEC (17/112), whereas all carcinoids and small cell carcinomas were consistently negative. Napsin A reactivity in LCNEC was focal in 12/17 cases, and weak or moderate in intensity in all cases, which was significantly lower in the extent and intensity than seen in adenocarcinomas (P<0.0001). The combination of TTF-1-diffuse/napsin A-negative or focal was typical of LCNEC but was rare in adenocarcinoma, and could thus serve as a helpful diagnostic clue. The diagnosis of napsin A-positive LCNECs was confirmed by classic morphology, diffuse labeling for at least one neuroendocrine marker, most consistently synaptophysin, and the lack of distinct adenocarcinoma component. Genomic analysis of 14 napsin A-positive LCNECs revealed the presence of mutations typical of lung adenocarcinoma (KRAS and/or STK11) in 11 cases. In conclusion, LCNECs are unique among lung neuroendocrine neoplasms in that some of these tumors exhibit low-level expression of exocrine marker napsin A, and harbor genomic alterations typical of adenocarcinoma. Despite the apparent close biological relationship, designation of adeno-like LCNEC as a separate entity from adenocarcinoma is supported by their distinctive morphology, typically diffuse expression of neuroendocrine marker(s) and aggressive behavior. Further studies are warranted to assess the clinical utility and optimal method of identifying adenocarcinoma-like and other subsets of LCNEC in routine practice.

Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.

BACKGROUND: RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. METHODS: We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. FINDINGS: Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12-49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. INTERPRETATION: The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. FUNDING: Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.

Diagnosis of thoracic SMARCA4-deficient undifferentiated tumor in cytology.

INTRODUCTION: Although alterations in SMARCA4-deficient occur in non-small cell lung carcinoma (SD-NSCLC), thoracic SMARCA4-deficient undifferentiated tumor (TSDUT) is recognized as a distinct entity in the 2021 World Health Organization Classification of Thoracic Tumors because of unique morphologic, immunophenotypic and molecular features, and worse survival compared with SD-NSCLC. Cytologic diagnosis of TSDUT is clinically important because of its aggressive behavior and because it is often diagnosed by fine-needle aspiration because TSDUTs are usually unresectable at presentation. Here, we identify cytologic features that can be used for recognition of TSDUT and distinction from SD-NSCLC. MATERIALS AND METHODS: Cytomorphologic features were investigated in cytology specimens from patients with TSDUT (n = 11) and compared with a control group of patients with SD-NSCLC (n = 20). RESULTS: The presence of classic rhabdoid morphology, at least focally, was entirely specific for TSDUT (n = 6, 55%) compared with SD-NSCLC (n = 0) in this study. TSDUT more frequently showed tumor necrosis (n = 11, 100% vs. n = 8, 40%; p = .001), dominant single-cell pattern on aspirate smears or touch preparation slides (n = 8 [of 9], 80% vs. n = 3, 15%; p = .010), nuclear molding (n = 5, 45% vs. n = 1, 5%; p = .013), and indistinct cell borders (n = 11, 100% vs. n = 5, 25%; P < .001) compared with SD-NSCLC, respectively. CONCLUSIONS: Cytomorphologic features occurring more frequently in TSDUT include tumor necrosis, dominant single-cell pattern, nuclear molding indistinct cell borders, and focal rhabdoid cells. Presence of these features in a cytology specimen of an undifferentiated tumor, particularly in a patient with a thoracic mass, should raise suspicion for TSDUT and prompt appropriate ancillary workup.

Sarcomas of the mediastinum with epithelioid morphology.

While soft tissue sarcomas typically have a spindled or pleomorphic appearance, a subset of malignant soft tissue neoplasms can have a prominent epithelioid morphology. In complex anatomic sites such as the mediastinum, such tumors can often be mistaken for a carcinoma or mesothelioma. Frequent expression of cytokeratin staining can further confound the diagnostic process and familiarity with these entities can help prevent an erroneous diagnosis. Particular entities that have been reported to occur in the mediastinum with such features include dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, SMARCA4-deficient thoracic sarcoma, alveolar soft part sarcoma and clear cell sarcoma. Many of these tumors exhibit unique clinical, genetic, molecular or immunohistochemical features which allow for accurate characterization. For example, pleomorphic liposarcoma contains bizarre appearing lipoblasts and dedifferentiated liposarcoma exhibits MDM2 gene amplification that is typically confirmed by fluorescence in-situ hybridization. Malignant peripheral nerve sheath tumor will often arise in association with a nerve or neurofibroma. Synovial sarcoma consistently exhibits rearrangements involving the SS18 gene and SMARCA4-deficient thoracic sarcoma shows loss of SMARCA4 staining in the tumor cells. Alveolar soft part sarcoma demonstrates an ASPL-TFE3 fusion transcript. Clear cell sarcoma often shows an EWSR1-ATF1 fusion transcript. When encountering a sarcoma of the mediastinum with epithelioid features, familiarity with these and other characteristics can help insure a correct diagnosis.

Percutaneous computed tomography guided biopsy of sub-solid pulmonary nodules: differentiating solid from ground glass components at the time of biopsy.

INTRODUCTION: This study assessed (i) the ability to identify the solid components of part-solid nodules (PSN) during computed tomography (CT) guided lung biopsy (CTGLB), (ii) the ability of CTGLB to assess the invasive nature of a nodule on pathology. MATERIALS AND METHODS: Sixty-nine nodules were studied in 68 patients who underwent CTGLB between 1/1/2014 and 10/31/2015. Diagnostic CT images and CTGLB images were reviewed. On diagnostic CT images, nodules were classified as ground glass nodules (GGN) or PSNs. Nodule size, location, and percentage of solid component were recorded. At the time of biopsy, the ability to visualize the solid component of a PSN, depth of lesion from skin, and ability to identify the needle within the solid component were recorded. RESULTS: There were 42 (61%) part-solid nodules and 27 (39%) GGNs. During biopsy, it was possible to differentiate the solid from the ground glass components in 35 (83%) PSNs. Fifty-nine (86%) nodules were neoplastic based on biopsy pathology (all non-small cell lung carcinoma). Thirty-nine (66%) were resected. In all cases biopsy pathology and surgical pathology agreed regarding the presence of lung carcinoma. In 6 (15%) cases biopsy pathology demonstrated purely lepidic growth but had some non-lepidic growth on surgical pathology, including 2 cases with acinar growth as a dominant pattern. CONCLUSION: In most patients, the solid and ground glass components of a PSN were distinguishable when performing a CTGLB. In a minority of patients, discrepancy was noted between biopsy pathology and surgical pathology regarding the invasive nature of a nodule.

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

PURPOSE: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. EXPERIMENTAL DESIGN: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). RESULTS: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001). CONCLUSIONS: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization.

INTRODUCTION: Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples. METHODS: The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3. RESULTS: ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1-; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1-/NEUROD1+; and (4) 14% ASCL1-/NEUROD1-. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17% were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine markerhigh/TTF-1high/DLL3high profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine markerlow/TTF-1low/DLL3low. CONCLUSIONS: This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.

The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer.

PURPOSE: SMARCA4 mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. EXPERIMENTAL DESIGN: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. RESULTS: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027). CONCLUSIONS: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.

SMARCA4-Deficient Thoracic Sarcomatoid Tumors Represent Primarily Smoking-Related Undifferentiated Carcinomas Rather Than Primary Thoracic Sarcomas.

INTRODUCTION: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non-small cell lung carcinomas (SD-NSCC). METHODS: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341-468 gene next-generation sequencing and other molecular platforms. RESULTS: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30-50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. CONCLUSIONS: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis.

INTRODUCTION: Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (1) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (2) effect of surgical margin-to-tumor diameter ratio in STAS-positive patients, and (3) potential utility of frozen sections (FSs) for detecting STAS intraoperatively. METHODS: We investigated 1497 patients who underwent lobectomy (n = 970) or sublobar resection (n = 527) for T1N0M0 lung ADC after propensity score matching. Outcomes were analyzed by using a competing risks approach. The effect of margin-to-tumor ratio on recurrence pattern (locoregional and distant) was investigated in patients who underwent sublobar resection. Five pathologists evaluated the feasibility of intraoperatively identifying STAS by using FSs (sensitivity, specificity, and interrater reliability). RESULTS: On multivariable analysis after propensity score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio = 2.84 [p < 0.001]) and lung cancer-specific death (subhazard ratio = 2.63 [p = 0.021]) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin-to-tumor ratio (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year cumulative incidence of recurrence rates were 16% and 25%, respectively); among patients without STAS, locoregional recurrences occurred in patients with margin-to-tumor ratio lower than 1 (a 5-year cumulative incidence of recurrence rate of 7%). The sensitivity and specificity for detecting STAS by use of FSs were 71% and 92%, with substantial interrater reliability (Gwet's AC1, 0.67). CONCLUSIONS: In patients with T1 lung ADC with STAS, lobectomy was associated with better outcomes than sublobar resection was. Pathologists can recognize STAS on FSs.

Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non-small cell lung cancer: A propensity-matched analysis.

OBJECTIVE: Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non-small cell lung cancer has not been extensively studied. METHODS: Patients with cT2-4N0-1M0 non-small cell lung cancer who received platinum-based chemotherapy were retrospectively identified. Exclusion criteria included stage IV disease, induction radiotherapy, and targeted therapy. The primary end point was disease-free survival. Secondary end points were overall survival, chemotherapy tolerance, and ability of Response Evaluation Criteria In Solid Tumors response to predict survival. Survival was estimated using the Kaplan-Meier method, compared using the log-rank test and Cox proportional hazards models, and stratified using matched pairs after propensity score matching. RESULTS: In total, 330 patients met the inclusion criteria (n = 92/group after propensity-score matching; median follow-up, 42 months). Five-year disease-free survival was 49% (95% confidence interval, 39-61) for neoadjuvant chemotherapy versus 48% (95% confidence interval, 38-61) for adjuvant chemotherapy (P = .70). On multivariable analysis, disease-free survival was not associated with neoadjuvant chemotherapy or adjuvant chemotherapy (hazard ratio, 1.1; 95% confidence interval, 0.64-1.90; P = .737), nor was overall survival (hazard ratio, 1.21; 95% confidence interval, 0.63-2.30; P = .572). The neoadjuvant chemotherapy group was more likely to receive full doses and cycles of chemotherapy (P = .014/0.005) and had fewer grade 3 or greater toxicities (P = .001). Response Evaluation Criteria In Solid Tumors response to neoadjuvant chemotherapy was associated with disease-free survival (P = .035); 15% of patients receiving neoadjuvant chemotherapy (14/92) had a major pathologic response. CONCLUSIONS: Timing of chemotherapy, before or after surgery, is not associated with an improvement in overall or disease-free survival among patients with cT2-4N0-1M0 non-small cell lung cancer who undergo complete surgical resection.

Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers.

KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-κB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed on prior clinical trials of bortezomib, both of whom had KRAS G12D-mutant NSCLC, prompting the initiation of this single-center phase 2 trial. Patients with advanced KRAS G12D-mutant NSCLC were eligible. Bortezomib was administered at 1.3 mg/m2 subcutaneously (days 1, 4, 8, 11; 21-d cycle) until progression or unacceptable toxicity. The primary objective was best objective response (RECIST v1.1). Sixteen patients with KRAS G12D-mutant lung adenocarcinomas were treated. Patients had a median pack year smoking history of 4 (range 0-45). A partial response (PR) was observed in one patient (-66% from baseline) and stable disease in five patients on the first stage of this study (overall response rate of 6%, 95% CI: 0.2-30.2), and further patients were not accrued. The median progression-free survival was 1 mo (95% CI: 1-6). The median overall survival was 13 mo (95% CI: 6-NA). The most common treatment-related adverse events were fatigue (38%) and diarrhea (26%). TP53 status did not predict response on exploratory testing. Of note, the patient with a PR had a unique subtype of lung adenocarcinoma-invasive mucinous adenocarcinomas (IMA)-and had rapid clinical improvement and substantial disease regression, which was also previously observed in two other patients with advanced KRAS G12D-mutant lung cancer with IMAs who received bortezomib on separate clinical trials. Exceptional responses to bortezomib can be achieved in KRAS G12D-mutant NSCLCs. KRAS G12D mutation alone, however, is not a robust predictor of response. Further evaluation should only be performed after further elucidation of other factors such as co-occurring alterations and histologic subtype such as IMA that may predict sensitivity to therapy.

What CT characteristics of lepidic predominant pattern lung adenocarcinomas correlate with invasiveness on pathology?

OBJECTIVES: The International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society lung adenocarcinoma classification in 2011 defined three lepidic predominant patterns including adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma. We sought to correlate the radiology and pathology findings and identify any computed tomography (CT) features which can be associated with invasive growth. MATERIALS AND METHODS: An institutional review board approved, retrospective study was conducted evaluating 63 patients with resected, pathologically confirmed, adenocarcinomas with predominant lepidic patterns. Preoperative CT images of the nodules were assessed using quantitative and qualitative radiographic descriptors while blinded to pathologic sub-classification and size. Maximum diameter was measured after evaluation of the axial, sagittal and coronal planes. Radiologic - pathologic associations were examined using Fisher's exact test, the Kruskal-Wallis test and the Spearman correlation coefficient (ρ). RESULTS AND CONCLUSION: Increasing maximum diameter of the whole lesion (ground glass and solid component) on CT was significantly associated with invasiveness (p = .003), as was the maximum pathologic specimen diameter (p = .008). Larger diameter of the solid component on CT was also found in lepidic predominant adenocarcinoma compared to minimally invasive adenocarcinoma (median 10.5 vs 2 mm, p = .005). More invasive tumors had higher visual estimated percentage solid component compared to whole lesion measurement on CT (p = .014). CT and pathologic measurements were positively correlated, although only moderately (ρ = .66) for the maximum whole lesion size and fair (ρ = .49) for solid/invasive component maximum measurements. Larger whole lesion size and solid component size of lepidic predominant pattern adenocarcinomas are associated with lesion invasiveness, although radiologic and pathologic lesion measurements are only fair-moderately positively correlated.

BRMS1 Expression in Surgically Resected Lung Adenocarcinoma Predicts Future Metastases and Is Associated with a Poor Prognosis.

INTRODUCTION: Expression of breast cancer metastasis suppressor 1 gene (BRMS1) is decreased in NSCLC cells and tumors. We hypothesized that intratumoral breast cancer metastasis suppressor 1 (BRMS1) expression is associated with lung adenocarcinoma (LUAD) histologic subtypes and overall survival (OS) and disease-free survival (DFS) in patients undergoing resection for early-stage LUAD. METHODS: Patients (N = 1030) who underwent complete resection for LUAD with tissue available for histologic evaluation were identified. Tissue microarrays were constructed, and immunostaining was performed and scored for intensity of BRMS1 expression. OS and DFS were estimated (by the Kaplan-Meier method) and compared between groups (by the log-rank test), stratified by stage. Hazard ratios (HRs) for hazard of death and recurrence were estimated using univariable and multivariable Cox proportional hazards models. OS and DFS nomograms were created, and model performance was examined. RESULTS: Intratumoral BRMS1 expression was high in 632 patients (61%) and low in 398 (39%). Low BRMS1 expression was associated with higher pathologic T stage (p = 0.001), larger tumor size (p ≤ 0.0001), greater lymphatic (p = 0.032) and vascular (p = 0.001) invasion, LUAD histologic subtype (p = 0.001), and intermediate and high architectural tumor grade (p = 0.003). Low BRMS1 expression was an independent predictor of worse OS (HR = 1.35, 95% confidence interval: 1.10-1.65, p = 0.004) and DFS (HR = 1.27, 95% confidence interval: 1.05-1.54, p = 0.012). OS and DFS nomograms showed excellent predictive performance based on discrimination and calibration. CONCLUSIONS: Among patients with surgically resected LUAD, OS and DFS were significantly worse in cases with low intratumoral BRMS1 expression. Our findings suggest that BRMS1 is an independent biomarker with prognostic significance in surgically resected LUAD.

Bronchiolar Adenoma: Expansion of the Concept of Ciliated Muconodular Papillary Tumors With Proposal for Revised Terminology Based on Morphologic, Immunophenotypic, and Genomic Analysis of 25 Cases.

We have identified 25 lesions involving alveolar lung parenchyma characterized by nodular proliferation of bland bilayered bronchiolar-type epithelium containing a continuous layer of basal cells. These lesions shared some histologic features with the recently described entity of ciliated muconodular papillary tumor (CMPT); however, the majority did not fit all diagnostic criteria in that they exhibited only focal or absent papillary architecture, and they had variable number of ciliated and mucinous cells, with some lesions entirely lacking 1 or both of these components. The morphologic and immunohistochemical features ranged from those resembling proximal bronchioles (proximal-type: moderate to abundant mucinous and ciliated cells; negative or weak TTF1 in luminal cells; n=8) to those resembling respiratory bronchioles (distal-type: scant or absent mucinous and ciliated cells; positive TTF1 in luminal cells; n=17). The hallmark of all lesions was a continuous layer of basal cells (p40 and CK5/6-positive). We provisionally designated these lesions as bronchiolar adenomas (BAs) and analyzed their clinicopathologic and molecular features. All BAs were discrete, sharply circumscribed lesions with a median size of 0.5 cm (range, 0.2 to 2.0 cm). Most lesions were either entirely flat (n=14) or contained focal papillary architecture (n=7); only 4 lesions, all proximal-type, were predominantly papillary, fitting the classic description of CMPT. Notably, of 9 lesions submitted for frozen section evaluation, 7 were diagnosed as adenocarcinoma. No postsurgical recurrences were observed for any lesions (median follow-up, 11 mo). Twenty-one BAs underwent next-generation sequencing and/or immunohistochemistry for BRAF V600E, revealing mutation profiles similar to those previously described for CMPTs, including BRAF V600E mutations (n=8, 38%), unusual EGFR exon 19 deletions (n=2, 10%), EGFR exon 20 insertions (n=2, 10%), KRAS mutations (n=5, 24%), and HRAS mutations (n=1, 5%). The mutation profiles were similar in proximal-type and distal-type lesions. In conclusion, we describe a family of putatively benign clonal proliferations with a spectrum of morphology recapitulating various levels of the bronchiolar tree, of which only a minor subset fits the classic description of CMPT. Comparable mutation profiles and partially overlapping morphologic features across the spectrum of these lesions support their nosological relationship. We propose designating this entire family of lesions as BAs, and that lesions currently designated CMPTs represent a subgroup of this family.

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers.

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676This article is highlighted in the In This Issue feature, p. 663.