The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).
Abstract Introduction: Cholangiocarcinoma (CCA) is a rare tumor accounting for less than 2% of all human malignancies. Mutations in the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex have been identified in approximately 20% of all human cancers and more than 40% of CCA. If the role of SWI/SNF on the tumor biology and microenvironment is being uncovered in other tumor types, it remains vastly unknown in CCA. Here, we wanted to investigate, using clinical samples, the association between SWI/SNF defects, the molecular landscape and tumor immune microenvironment in CCA. Material and Methods: Mutation profiling of 103 patients with CCA from Gustave Roussy (GR) was assessed with FoundationOne® CDx 324-gene NGS panel. Formalin-fixed paraffin-embedded tumor tissues from 11 patients with CCA were analyzed for SWI/SNF (PBRM1, ARID1A, SMARCB1 and SMARCA4) and Polycomb-DUB (BAP1) subunits, as well as lymphocytic markers (CD4 and CD8). Stainings were performed using a VENTANA BenchMark ULTRA. Absolute count of positive cells per mm2 was determined by digital image analysis with the Definiens Developer XD™ by selecting at least 5 independent tumoral zones. Pairwise comparisons were performed using the Mann-Whitney test. Results: Among the patients for whom NGS data was available, the most frequently altered genes were TP53 (27%), CDKN2A (17%), KRAS (16%), ARID1A (12%), FGFR2 (12%) and PBRM1 (10%). Subunits of the SWI/SNF complex and BAP1 were mutated in 25% and 10% of cases, respectively. Tumor samples with ARID1A mutations (n=5) showed strongly decreased ARID1A expression compared to WT tumor samples (n=2) (mean = 308.03 positive nuclei (p.n)/mm2 versus 6096.82 p.n/mm2 respectively; P<0.0001) but unchanged PBRM1, SMARCB1 and SMARCA4 expression. PBRM1 mutations (n=4) were associated with decreased expression of PBRM1 (mean = 309.6 p.n/mm2 versus 4980.2 p.n/mm2 in WT samples; P<0.0001) and ARID1A (mean=1196.15 p.n/mm2; P<0.001), but unchanged SMARCB1 and SMARCA4 expression. BAP1 mutations (n=3) were also associated with decreased BAP1 and ARID1A expression (ARID1A mean = 457.70 p.n/mm2; P<0.001). ARID1A and PBRM1-altered tumor samples showed a poorly infiltrated microenvironment, with decreased CD4+ T cell (159.48 positive cells (p.c)/mm2 and 188.66 p.c/mm2 respectively versus 1126.52 p.c/mm2 for WT; P<0.0001) and CD8+ T cell density (72.38 and 76.54 p.c/mm2 versus 548.58 p.c/mm2 for WT; P<0.0001). Conclusion: Mutations in the ARID1A and PBRM1 subunits of the SWI/SNF complex are associated with a loss of protein expression. In contrast to what reported in other tumor types, ARID1A and PBRM1 mutations correlated with poorly lymphocytic TIME in CCA. Decreased PBRM1 expression is further associated with decreased ARID1A expression. Independent revalidation and further study in larger tumor series are warranted. Citation Format: Clémence Astier, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, Sophie Postel-Vinay. Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5714.
ABSTRACT Background Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFβ with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFβ participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations. Methods We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer. Results We demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta (IFNβ) expression in tumor-associated macrophages (TAMs) within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and inhibition of immune exclusion observed with the combination of MT1 and RT were dependent on type I interferon signaling. Conclusions These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.
<p>Performances of the deep-learning cell detection model in TCGA cohorts (oral cavity, uterine cervix and larynx SCC) and GR cohorts (oral cavity SCC)</p>
This study aimed to correlate 18F-FB-mini-PEG-E[c(RGDyK)](2) (18F-FPRGD2) uptake to integrin αvβ3 expression and angiogenesis in renal tumors. Methods:18F-FPRGD2 PET/CT was performed on 27 patients before surgical resection (median 4 d) of a renal mass. The 18F-FPRGD2 uptake was compared with integrin αvβ3, CD31, CD105, and Ki-67 using immunohistochemistry; with placental growth factor and vascular endothelial growth factor receptors 1 and 2 using reverse transcription polymerase chain reaction; and with vascular endothelial growth factor A isoforms using enzyme-linked immunosorbent assay. Results: Overall, 18F-FPRGD2 uptake significantly correlated (P < 0.0001) with integrin αvβ3 expression in renal masses. However, it correlated only with integrin αvβ3-positive vessels in the group of papillary carcinomas whereas it correlated with integrin αvβ3 expression by tumor cells in the clear cell carcinoma group. Conclusion:18F-FPRGD2 uptake reflects the expression of integrin αvβ3 in renal tumors but represents angiogenesis only when tumor cells do not express the integrin.
535 Background: Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have emerged as a successful immunotherapeutic strategy for advanced and metastatic urothelial cancer (UC). Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies leads to durable tumor regressions in up to 25% metastatic muscle invasive UC (MIBC). Neoadjuvant use of ICI also showed remarkable efficacy and represents a unique opportunity to study immunodynamics during PD-1 blockade to decipher functional predictors of response and resistance. Methods: Patients diagnosed with T2-T4aN0M0 MIBC were treated with 3 cycles of neoadjuvant pembrolizumab before cystectomy in the PANDORE trial (NCT03212651). The primary endpoint was pathologic complete response (ypT0N0). Secondary endpoints focused on safety, progression-free survival (PFS) and biomarker analysis. We performed longitudinal analysis of peripheral and tumor infiltrating lymphocytes, tumor microbiome as well as soluble factors using high dimensionnal immune phenotyping by mass cytometry, immuno-fluorescence and -histochemistry and multiplex immunoassays. Humoral and cellular recall immune memory against urinary tract commensals were studied. Results: Thirty-nine patients were enrolled from October 2017 to December 2019. All but 5 (n = 34 patients (87.2%)) proceeded with cystectomy. Ten patients presented with ypT0N0 (29.4%; 95% CI: 15.1 %-47.5 %). Multidimensional biomarkers analysis showed that baseline follicular T helper (Tfh) and post-pembrolizumab tertiary lymphoid structure (TLS) and activated B cells were associated with outcome ( p= 0.005, p= 0.01 and p= 0.04, respectively). Plasma CXCL13 (the prototypic chemokine secreted by Tfh and involved in TLS functions) increased after 1 cycle of PD-1 blockade in responders and patients without progression at 24 months ( p= 0.002 and p= 0.0001, respectively). Focusing on MIBC tumor microbiome, we showed that intracellular Gram negative bacteria and other commensals were more frequent in tumoral than in normal urothelium ( p= 0.04). Interestingly, basal CXCL13-secreting CD4 + T cells and IgG directed against urinary pathobionts such as Escherichia coli predicted prolonged PFS ( p= 0.01 and p= 0.001, respectively). Conclusions: Our results suggest that urothelial commensals could induce specific Tfh and B cell responses that were re-invigorated by PD-1 blockade and associated with clinical benefit to pembrolizumab. Further analyses are needed to validate the predictive value of commensal-specific Tfh in UC and other epithelial cancers that are directly or indirectly exposed to bacteria. Clinical trial information: NCT03212651.
Abstract Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC)—a type of macrophages—in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative chemotherapy–treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the antitumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor-associated macrophages, which colocalized in keratin tumor niches. Significance: Novel individual biomarkers are needed to guide therapeutic decisions for patients with head and neck cancer. We report for the first time, granulomas of TREM2-expressing multinucleated giant macrophages in keratin-rich tumor niches, as a biomarker of favorable prognosis and developed a deep-learning model to automate its quantification on routinely stained pathological slides.
