Search

Breast cancer metastases to the gastrointestinal tract are very rare occurrences. Among the histological subtypes of breast cancer, invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach. Conversely, there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma. Herein, we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient, particularly focusing on the clinical and pathological features of presentation. Moreover, we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20, cytokeratin 7, estrogen receptor, progesterone receptor, E-cadherin, gross cystic disease fluid protein 15, and GATA binding protein 3 for an accurate differential diagnosis.

9077 Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.

9568 Background: Patients with non-small cell lung cancer (NSCLC) and a poor Eastern Cooperative Oncology Group performance status (ECOG PS) have been excluded from immunotherapy clinical trials. We sought to evaluate clinical outcomes to first-line pembrolizumab in patients with advanced NSCLC, a PD-L1 tumor proportion score (TPS) of ≥50%, and an ECOG PS of 2. Methods: We performed a multicenter retrospective analysis of patients with metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% (negative for genomic alterations in EGFR and ALK) who received treatment with first-line commercial pembrolizumab. Clinical outcomes were compared in patients based on ECOG PS. Results: Among 234 patients, 83.3% (N = 195) had an ECOG PS of 0 or 1, and 16.7% (N = 39) had an ECOG PS of 2. The baseline clinicopathological characteristics were balanced between the ECOG PS 0-1 vs 2 groups in terms of age, sex, tobacco use, histology, KRAS mutation status, presence of other potentially targetable driver mutations ( BRAF, MET, HER2, RET), history of central nervous system (CNS) disease, and PD-L1 TPS distribution. Compared to patients with an ECOG PS of 0-1, patients with an ECOG PS of 2 had a significantly lower objective response rate (ORR 43.1% vs 25.6%; P = 0.04), a numerically shorter median progression free survival (mPFS 6.6 months vs 4.0 months; P = 0.09), and a significantly shorter median overall survival (mOS 20.3 months vs 7.4 months; P < 0.001). Upon disease progression, patients with an ECOG PS of 2 were significantly less likely to receive second-line systemic therapy compared to patients with an ECOG PS of 0-1 (55.5% vs 14.3%, P < 0.001). Conclusions: Although a subset of patients with an ECOG PS of 2 can respond first-line pembrolizumab, clinical outcomes in this population are poor, and use of second-line systemic therapy is infrequent.

Purpose Solitary fibrous tumor (SFT) of the pleura is a rare mesenchymal neoplasm arising from mesenchymal cells in the areolar tissue subjacent to the mesothelial-lined pleura and accounting for less than 5% of primary pleural tumors. SFTs are generally benign and asymptomatic, with 10-year survival rates of up to 98%. Unfortunately, approximately 10% have malignant potential, leading to local recurrence after radical surgery and/or metastatic spread. Of note, giant pleural SFT, which consists of a tumor occupying at least 40% of the affected hemithorax, is even less common with only anecdotal cases reported in the medical literature. Methods We describe a unique case of giant SFT of the pleura that metastasized to the thyroid gland 1 year after complete resection, focusing on its clinical and pathological features of presentation. Results En bloc resection remains the mainstay of therapy with curative intent. Patients with large tumors may undergo preoperative angiography with percutaneous embolization of the tumor, which allows to reduce perioperative bleeding. In case of local recurrence, surgery still remains the best treatment option. However, surgery can also be considered in patients with isolated metastatic spread. Conclusions Every suspected and proven SFT of the pleura should undergo surgical resection, as clinical and radiological criteria cannot accurately distinguish benign from malignant forms. Moreover, the peculiar histological features of SFT should not be neglected when planning clinicoradiological follow-up. Additionally, suspicious clinical findings during follow-up should always be thoroughly investigated in order to exclude or confirm the diagnosis of recurrent disease.

e15113 Background: STK11 mutations ( STK11m) have been associated with resistance to ICI in KRAS-mutant ( KRASm) NSCLC. Whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) NSCLC is unknown. Methods: We analyzed clinical outcomes of patients (pts) with NSCLC treated with ICI according to KRAS and STK11 mutation status in independent discovery (DFCI+MGH) and validation (MSKCC) cohorts. TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/ STK11 co-mutation status. Results: Of 1195 pts with advanced nonsquamous NSCLC treated with ICI, 447 (37.4%) had a KRASm, 252 (21.1%) had pathogenic STK11 mutations, and 128 (10.7%) had concurrent KRASm and STK11m. ICI outcomes for the discovery and validation cohorts in KRASm and KRASwt cases by STK11 mutation status are shown in Table. In the combined cohort (discovery+validation), STK11m was associated with significantly worse outcomes to ICI among KRASm cases: ORR 10.2% vs 30.7%, P < 0.001; median progression-free survival (mPFS): 2.0 vs 4.8 months (mo), HR:0.49 [95%CI:0.39-0.61], P < 0.0001; median overall survival (mOS): 6.1 vs 16.9 mo, HR:0.50 [95%CI:0.39-0.63], P < 0.0001. In multivariable analysis, STK11m was associated with significantly shorter PFS (HR:0.56, P = 0.002) and OS (HR:0.57, P = 0.006). By contrast, STK11m had no impact on ICI outcomes among KRASwt cases: ORR 24.2% vs 19.2%, P = 0.21; mPFS: 2.5 vs 2.8 mo, HR:0.98 [95%CI:0.79-1.21], P = 0.89; mOS: 12.0 vs 11.5 mo, HR:1.06 [95%CI:0.85-1.33], P = 0.57. Among KRASwt cases, STK11m had no impact on ICI outcomes among both smokers and never smokers, when analyzed separately. Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt NSCLC, STK11m was associated with the downregulation of MHC class II-related genes (P = 0.02). Cell subset transcriptome analysis showed significantly lower proportions of M1 macrophages among KRASm/ STK11m but not among KRASwt/ STK11m NSCLCs (P < 0.01). Conclusions: STK11m are associated with resistance to ICI in KRASm but not KRASwt NSCLC. STK11m/ KRASm vs STK11m/ KRASwt NSCLC have distinct immunophenotypes. [Table: see text]

9042 Background: MET exon 14 alterations occur in ~3% of patients (pts) with NSCLC. Although clinical and genomic features of MET exon 14 mutant (mut) NSCLC are better characterized in the metastatic setting, less is known about early-stage disease for this molecular subtype. Methods: Clinicopathologic and genomic data were collected from patients (pts) with resected stage I-III MET exon 14 mutant NSCLC at the Dana-Farber Cancer Institute (DFCI) and the Memorial Sloan Kettering Cancer Center (MSKCC). We estimated the disease-free survival (DFS) and overall survival (OS) of patients from the date of surgical resection. The prevalence of MET exon 14 mutations in stage I-III NSCLC was assessed using OncoPanel NGS v3.0 at DFCI. Results: The prevalence of MET exon 14 alterations in resected tumors of pts with stage I-III NSCLC at DFCI using Oncopanel v3 was 2.8% (17/613) overall: 2.9% (16/542) in non-squamous and 1.4% (1/71) in squamous histology. We identified 131 pts with resected stage I-III (I = 73, II = 28, III = 30) MET exon 14 mut NSCLC at DFCI (Oncopanel v1-v3) and MSKCC (MSK-IMPACT), with a median age of 71 years (yrs) (range: 43-88). There were no significant differences in sex, smoking status, or type of MET alteration across stages. In stage I resected tumors there was a higher proportion of adenocarcinoma histology compared to stages II and III (p = 0.009). The median harmonized TMB (mTMB) was similar across stages (p = 0.43). Common genomic co-alterations included MET amplification (amp) (5.3%), CDK4/ 6 amp (19.1%), MDM2 amp (35.1%), TP53 mut (17.6%) and CDKN2A/ B loss (9.2%). The median DFS in stage I, II, and III NSCLC was 8.3 yrs (95% CI: 3.1-8.3), 2.6 yrs (95% CI: 1.0-2.6), and 2.1 yrs (95% CI: 0.7-2.7), respectively (p = 0.017). The median OS in stage I, II, and III NSCLC was 9.2 yrs (95% CI: 8.5 -10.5), not reached (NR) (95% CI: NR-NR), and 4.1 yrs (95% CI: 3.6-4.1), respectively (p = 0.052). Concurrent MET amp was independently associated with worse DFS (HR: 4.9, 95% CI: 1.8-13.1; p = 0.002) in multivariate analysis. Conclusions: MET exon 14 mutations are present in 2.8% of resected stage I-III NSCLCs. Given the prevalence of this molecular alteration in early-stage NSCLC, clinical trials exploring the role of adjuvant and neoadjuvant MET targeted therapies in this population may be warranted.