FGFR1 Amplification Research Articles

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors—alterations (mutations and fusions), amplification and mRNA/protein overexpression—but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The Role of ctDNA in Real-World Practice.

Simple SummaryThe analysis of circulating tumour DNA (ctDNA) can help to identify genetic alterations present in cancer cells without the need to access tumour tissue, which can be an invasive approach. This study explored the feasibility of analysing ctDNA in patients with advanced well-differentiated neuroendocrine tumours (WdNETs). A total of 45 patients (15 with WdNETs) were included. Although feasible (with a non-evaluable sample rate of 27.8%), mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.Background: The role of tumour genomic profiling in the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate for tumour tissue when the latter is insufficient for analysis. Methods: Patients diagnosed with WdNETs underwent ctDNA genomic profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly-differentiated neuroendocrine carcinoma) were used for comparison. The aim was to determine the rate of: test failure (primary end-point), “pathological alterations” (PAs) (secondary end-point) and patients for whom ctDNA analysis impacted management (secondary end-point). Results: Forty-five patients were included. A total of 15 patients with WdNETs (18 ctDNA samples) were eligible: 8 females (53.3%), median age 63.2 years (range 23.5–86.8). Primary: small bowel (8; 53.3%), pancreas (5; 33.3%), gastric (1; 6.7%) and unknown primary (1; 6.7%); grade (G)1 (n = 5; 33.3%), G2 (9; 60.0%) and G3 (1; 6.7%); median Ki-67: 5% (range 1–30). A total of 30 patients with non-WdNETs (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs. 17.65% in non-WdNETs; p-value 0.395). Of the 13 WdNET samples with successful ctDNA analyses, PAs were detected in 6 (46.15%) (vs. 82.14% in non-WdNETs; p-value 0.018). In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs. 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. These were: CDKN2A mutation (mut) (one sample), CHEK2mut (one), TP53mut (one), FGFR2 amplification (one), IDH2mut (one), CTNNB1mut (one), NF1mut (one) and PALB2mut (one). None were targetable (0%) or impacted clinical management (0%). There was a lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs. non-WdNETs (mean 26.99), even though differences did not reach statistical significance (p-value 0.0584). Conclusions: Although feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rates of PAs and mMAFs were higher in non-WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.

Abstract P1-18-35: Futibatinib in combination with fulvestrant in patients with metastatic breast cancer (MBC) harboring high-level FGFR1 amplification: Preliminary data from a phase 2 study

Abstract Background: FGFR gene amplifications are found in 18% of breast cancers (BCs), with FGFR1 amplifications occurring in ≈10% of cases, predominantly in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) MBCs. FGFR1 amplifications are associated with resistance to endocrine therapy, and in preclinical experiments, FGFR pathway inhibition has been shown to overcome resistance to hormone therapy in BC harboring FGFR1 amplifications. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown preclinical activity in BC xenograft models harboring FGFR1/2 amplifications. In a phase 1 study, futibatinib showed promising clinical activity and tolerability across tumor types, including MBC, harboring various FGFR aberrations. A multicohort phase 2 trial (FOENIX-MBC2; NCT04024436) was designed to evaluate futibatinib alone (cohorts 1-3) or in combination with fulvestrant (cohort 4) in patients with MBC harboring FGFR2 or FGFR1 amplifications, respectively. Here, we report preliminary safety data from cohort 4 of FOENIX-MBC2, including data from a safety lead-in. Methods: Cohort 4 of FOENIX-MBC2 enrolled adult patients with HR+ HER2− MBC harboring high levels of FGFR1 amplification (FGFR1:CEN8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell), Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function. Patients were fulvestrant naive and had previously received 1-2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a CDK4/6 inhibitor (if eligible). Cohort 4 began with a safety lead-in to assess dose-limiting toxicities (DLTs) during the first treatment cycle. Patients received oral futibatinib 20 mg once daily continuously, and intramuscular fulvestrant 500 mg was administered on days 1 and 15 of cycle 1 and day 1 of every subsequent 28-day cycle. Patients were treated until disease progression, unacceptable toxicity, or another discontinuation criterion was met. Results: As of data cutoff (March 31, 2021), cohort 4 had enrolled 8 female patients with HR+ HER2− MBC harboring high-level FGFR1 amplification. The median age was 55.5 years (range: 31-62 years), and all patients had received ≥2 prior therapies for advanced/metastatic BC. The median duration of treatment was 8.0 weeks (range: 3.0-32.7 weeks); 3 of 8 patients (38%) were continuing treatment at time of data cutoff. All patients experienced treatment-related adverse events (TRAEs; grade ≥3: 25%). The most common TRAE was hyperphosphatemia (88%), followed by constipation (62%), transaminase elevation (50%), dry mouth (38%), and alopecia (38%). Among these TRAEs, grade ≥3 events were only reported for hyperphosphatemia (12%), and no serious adverse events were reported. In this cohort, TRAEs led to dose reductions in 4 patients, dosing interruptions in 3 patients, and treatment discontinuation in 1 patient; no patients died due to TRAEs. DLTs were evaluated in 5 patients following 1 treatment cycle (1 patient was enrolled after data cutoff, and 4 of 9 patients were not evaluable for DLTs); DLTs were not experienced by any of the 5 evaluable patients. Conclusions: Based on these preliminary safety results, the combination of futibatinib and fulvestrant appears to be safe and tolerable in patients with HR+ HER− MBC harboring high-level FGFR1 amplification. The safety profile was consistent with the individual profiles of both drugs, and the treatment combination did not appear to result in synergistic toxicity. As no DLTs were observed in 5 evaluable patients, the recommended futibatinib dose in combination with fulvestrant is 20 mg once daily. Efficacy will be evaluated in the complete 28-patient post-lead-in cohort, in which enrollment is ongoing. Citation Format: Senthil Damodaran, Nisha Unni, Karthik V. Giridhar, Brooke Daniel, Sacha Howell, Luis Costa, Marta Ferreira, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Futibatinib in combination with fulvestrant in patients with metastatic breast cancer (MBC) harboring high-level FGFR1 amplification: Preliminary data from a phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-35.

Abstract P5-07-06: Genomic characterization and tumor evolution in matched(primary-relapse)samplesof patients with METAPLASTIC breast cancer

Abstract Introduction and objectives. Metaplastic breast cancer is an heterogenous and infrequent disease (0.5-2%). Histologically, it is defined by differentiation of neoplastic epithelium into squamous or mesenchymal-like elements. Although they are mainly triple negative tumors, they present a more aggressive course with less response to chemotherapy and worse prognosis. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) samples of patients (pts) with metaplastic breast cancer. Material and Methods. Genomic profiling of tumor biopsies from different time points in patients with early-stage metaplastic breast cancer who had disease recurrence/progression, and were treated at our institution between 2010 and 2020. Tumor samples were analyzed by DNA- Next Generation Sequencing (NGS; Illumina 2x75bp) using the ActionOncoKitDX panel (Imegen-Health in Code group). It allowed the study of point mutations in 50 genes, CNVs, fusion genes among 8 genes and pharmacogenetic SNPs associated with treatment efficacy or toxicity. It also determined MSI through 110 markers. The results were classified following the recommendations of the ACMG (American College of Medical Genetics). Only pathogenic and likely pathogenic variants were considered for analysis and afterwards we categorized them following the ComPerMed (The Personalized Medicine Commission) criteria. Results. We have analyzed 21 matched diagnosis-relapse tumor samples (8 primary tumor samples, and 13 loco-regional or metastatic disease) from 8 patients. In 4 patients, genomic characterization was performed at 3 different time points of their tumor evolution. Pathogenic alterations identified were mutations in TP53 (in 100% of the samples), TERT promoter (29%), and MYC amplifications (24% of samples, of which 75% were relapse/progression samples). We didn’t find any mutation in PI3KCA, but PTEN was found to have variations in 38% samples (10% mutations and 38% deletions). Amplification of FGFR1 was identified in 13% of the pts (only in the primary tumor). No ERBB2 or EGFR gene amplifications were detected, neither high grade MSI. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in the former ones. Sixty three percent of the cases were Tier I and II category alterations, which could have future implications in the management of this neoplasia. Conclusion. In our series of metaplastic carcinoma, the most frequent pathogenic alterations occurred in cycle regulation’s genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were enriched in MYC amplification and inTP53 allelic frequency. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients. Citation Format: Mónica Cejuela, Agostina Stradella, Anna Petit, Pablo Gargallo, Jan Bosch, Paula Carbonell, Sabela Recalde, Andrea Vethencourt, Adela Fernández, Catalina Falo, Miguel Gil-Gil, Silvia Vazquez, Rafael Villanueva, Teresa Soler, Inés Calabria, Sonia Pernas. Genomic characterization and tumor evolution in matched(primary-relapse)samplesof patients with METAPLASTIC breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-06.

Abstract P2-07-02: Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC)

Abstract Background: Endocrine therapy with CDK 4/6 inhibitors (ET/CDK4/6i) represents the 1st line therapy for ER+/HER2- ABC. While majority of patients derive clinical benefit with combination therapy, a subset have refractory disease with progression within 6 months. However, predictive biomarkers for rapid progression are lacking. In this study, we evaluated genomic profiles associated with rapid disease progression on ET/CDK4/6i. Methods: We identified 77 patients who received 1st line ET/CDK4/6i combination therapy (AI or SERD with one of the 3 approved CDK4/6is) and had ctDNA analysis performed via plasma based genotyping utilizing the commercially available Guardant360 assay at three sites: Washington University in St. Louis, MO, Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). We aimed to look at the differences in patient characteristics and genomic profiles of the tumors assessed from baseline ctDNA specimens between the patients with rapid progression (time to progression TTP<=6 months) vs others. In particular, we focused on growth factor receptors (FGFR, EGFR) given that previous studies have shown that activation of FGFR1 and EGFR signaling may be implicated in resistance to endocrine based therapy in breast cancer. Time to progression was estimated by using Cox regression. Variable associations were estimated via logistic regression. Results: In the combined cohort, FGFR1 amplification (FGFR1amp) was detected in 15/77 patients (19.5%). FGFR1amp was seen in 5/10 (50%) of patients with rapid progression, consistent with existing knowledge that FGFR1amp contributes to resistance to CDK4/6i and/or ET. Presence of FGFR1amp was independently associated with shorter TTP (11.2 vs. 34.7 months, HR=3.14, p=0.02). EGFR mutations (EGFRmut) were detected in 8/77 (10.4%) patients, 3 of which were found among patients with rapid progression and another 5 among those with TTP<=15 months. Presence of EGFRmut was also associated with shorter TTP (8.5 vs. 31.7 months, HR=6.50, p<0.001) in multivariable analysis. Of the 4 patients with shortest TTP (<3 months) 3 harbored both FGFR1amp and EGFRmut. In another 3 patients we observed FGFR1amp and co-activation of genes implicated in G1/S phase cell cycle transition, suggesting that FGFR1 amplified cells may require a co-activating downstream event that ultimately, via multiple pathway cross-talk, renders them resistant to ET/CDK4/6 inhibition. Patients with FGFR1 amplified tumors were younger compared to those without FGFR1amp (54.3 vs. 62.7 years, p=0.04). Presence of FGFR1amp was associated with presence of liver (p=0.01) but not bone or lung metastases which could be one of the explanations why patients with higher liver tumor burden are more resistant to ET/CDK4/6i inhibition. PIK3CA and TP53 gene mutations in our cohort were frequent (found in 41% and 30% of the patients, respectively) but were independently not associated with TTP (PIK3CAmut+ HR=1.31, p=0.55, TP53mut+ HR=0.67, p=0.36). ESR1 mutations were rarely encountered (9%) as the cohort had only been exposed to adjuvant endocrine therapy. Conclusions: These findings highlight how ctDNA can be used for patient stratification prior to initiation of first line of therapy in ER+/HER2- ABC since it is evident that not all patients derive the same benefit from ET/CDK4/6i. Certain genomic alterations, particularly in FGFR1, EGFR, and G1/S phase cell cycle transition are associated with rapid progression to 1st line ET/CDK4/6i therapy, and highlight the need for clinical trials investigating combination/novel therapies for this subgroup of patients with HR+/HER2- ABC. Our findings are hypothesis-generating and require further exploration in larger datasets. Citation Format: Marko Velimirovic, Lorenzo Gerratana, Andrew A Davis, Whitney L Hensing, Katherine Clifton, Ami N Shah, Paolo D'Amico, Charles S Dai, Elyssa N Denault, Cynthia X Ma, Seth A Wander, Dejan Juric, Massimo Cristofanilli, Bruce A Chabner, Aditya Bardia. Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-02.

Abstract P3-08-07: Comparison of the genomic alterations in metastatic inflammatory and non-inflammatory breast cancer

Abstract Background:. Inflammatory breast cancer (IBC) represents a rare (~1-5% of all breast cancers, BC) and particularly aggressive type of BC, accounting for roughly 10% of BC-related mortality annually. So far IBC has been mainly characterized at the genomic level using samples from the primary tumor. Here, using publicly available data from two large cohorts, we compared the genomic alterations in primary and metastatic samples from patients with metastatic IBC to alterations in samples of patients with metastatic non-IBC. Patients and methods:. We retrieved publicly available clinical and genomic data from primary (P) and metastatic (M) samples from MSK-IMPACT (MSK) and the Metastatic Breast Cancer project (MBC) from cbioportal. IBC was defined as cT4d. We considered female metastatic patients with invasive BC of no special type (commonly referred to as invasive ductal BC): 34 patients with IBC and 602 with non-IBC. To focus on alterations with potential clinical relevance, we only retained the genomic alterations annotated as oncogenic by OncoKB. We applied Firth logistic regression adjusted for hormonal receptor status (positive vs negative), HER2 status (positive vs negative) stage (II vs I, III vs I, IV vs I) and cohort (MSK vs MBC) with genomic alterations or metastatic sites as outcome variables and IBC status as independent variable (yes vs no). A minimum of 5 patients harboring the alterations were required to perform the analysis. Chromosomal instability (CIN) score and Tumor Mutational Burden (TMB) were investigated by linear regression and quantile regression respectively, adjusted as described above and considering the median for the latest. P and M samples were analyzed separately, a patient was considered as ‘having’ the alteration if at least one of her samples was altered. All analyses were performed in R 4.0.2. Results:. Metastatic samples from chest wall and skin metastases were significantly more represented in patients with IBC as compared to patients with non-IBC (Adjusted Odds Ratio (ORadj): 6.16, 95% confidence interval (95CI): [1.94-18.38], p-value: .003 and ORadj: 7.60, 95CI: [1.66-30.05], p-value: .012 respectively), which is in line with the course of the IBC disease. Several studies have suggested IBC to have a higher TMB than non-IBC. Here we confirmed an increase in TMB in P and M IBC (Adjusted coefficient (coefadj): 3.00, 95CI: [1.60-4.20], p-value: .003 and coefadj: 4.00, 95CI: [0.85-4.15], p-value<.001). On the contrary, we did not observe an increase in CIN score in patient with IBC as compared to patient with non-IBC, both when considering P and M samples (coefadj: -.001, 95CI: [-0.10;0.09], p-value: .877 and coefadj: -.05, 95CI: [-0.16;0.05], p-value: .330 respectively). With regard to the genomic alterations, we observed an increased frequency of TP53 mutations as well as amplifications of AURKA and FGFR1 in patients with IBC versus patient with non-IBC both considering P and M samples (Table 1). We also observed an increased prevalence of PIK3CA and GATA3 mutations in patients with IBC versus non-IBC in the M samples only. Conclusion:. While the results need to be validated in additional patient series, these could be of potential clinical relevance given the higher incidence of treatment targets (AURKA amplifications, PIK3CA mutations) and markers of treatment resistance (FGFR1 amplifications) present in IBC versus non-IBC in patients with metastatic disease. Table 1.Patients with primary samples. (279 patients with clinical information available - 279 samples)Patients with metastatic samples. (311 patients with clinical information available - 339 samples)AlterationAlteration countOR [95CI]p-valueAlteration countOR [95CI]p-valueTP53 mutation4120.18 [4.95-96.38]<.0013511.30 [3.68 - 37.05]<.001PIK3CA mutation106.00 [0.76-40.27].085156.35 [1.58-22.61].011GATA3 mutation85.10 [0.49-30.63].147610.95 [1.59 - 62.80].018AURKA amplification539.33 [5.26-490.37]<.001517.28 [2.76-119.06]<.001FGFR1 amplification98.99 [1.81-40.52].009714.08 [2.63-71.46]<.001 Citation Format: François Richard, Maxim De Schepper, Marion Maetens, Sophia Leduc, Edoardo Isnaldi, Tatjana Geukens, Karen Van Baelen, Ha-Linh Nguyen, Peter Vermeulen, Steven Van Laere, Luc Dirix, Giuseppe Floris, Elia Biganzoli, Christine Desmedt. Comparison of the genomic alterations in metastatic inflammatory and non-inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-07.

Abstract P5-08-12: Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations

Abstract Purpose: Several FGFR alterations have been found in breast cancer, however, their role as a therapeutic target in breast has been controversial. Futibatinib (TAS-120; Taiho) is a novel, selective pan-FGFR inhibitor which irreversibly binds to and inhibits FGFR1-4 at nanomolar concentrations. We sought to determine the efficacy of futibatinib in breast cancer models with differing FGFR alterations. Experimental Design: In vivo, antitumor efficacy was evaluated by tumor growth curves and event-free survival in a panel of patient-derived xenografts (PDXs) from breast cancer patients with different FGFR1-4 alterations. Genomic alterations in the PDXs were characterized by next generation sequencing. Correlation of FGFR gene expression in matched patient tumors and PDXs was analyzed by RNA sequencing. In vitro, FGFR2 Y375C mutant and FGFR2-BICC1 fusion expressing MCF10A cell lines were generated, and effect on cell proliferation, colony formation assay, and cell signaling was assessed with and without futibatinib. Frequency of FGFR mutations and FGFR2 amplification was compiled from internal and public databases. Results: Breast cancer PDXs varied in their expression of FGFR1-4. FGFR gene expression significantly correlated between matched patient tumors and PDXs derived from them, however, PDXs had higher levels of FGFR3 and FGFR4 expression compared to patient samples. Futibatinib inhibited tumor growth in three of 10 PDX models, with tumor stabilization in a FGFR2 amplified model and prolonged tumor regression (more than 110 days) in a PDX bearing a FGFR2 Y375C mutation. In vitro, expression of FGFR2 Y375C, as well as FGFR2-BICC fusion in normal-like MCF10A cells enhanced growth, colony formation ability and FGFR signaling. Cells expressing FGFR2 Y375C as well as FGFR2-BICC fusions were more sensitive to futibatinib. In the five breast cancer genomic series we analyzed, FGFR2 mutations and amplifications were found in 1.1%-2.6% and 1.4%-2.5%, respectively. Conclusions: Futibatinib had single agent activity of selected breast cancer PDX models. FGFR2 activating mutations and amplification may represent rare but promising therapeutic targets to FGFR inhibition. Citation Format: Turcin Saridogan, Argun Akcakanat, Ming Zhao, Kurt W. Evans, Erkan Yuca, Stephen Scott, Bryce P. Kirby, Xiaofeng Zheng, Senthil Damodaran, Funda Meric-Bernstam. Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-12.

Abstract OT2-19-02: Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients

Abstract Background: Abemaciclib is a drug approved for ER-positive and HER2-negative metastatic or recurrent breast cancer and those treatable in an early setting. Some patients with ER-positive and HER2-negative breast cancer pretreated with abemaciclib and endocrine therapy may still benefit from abemaciclib rechallenge, especially in case of acquired resistance to endocrine therapy. However, there is no evidence for abemaciclib rechallenge. To address this, a single-arm phase 2 trial is planned to determine whether abemaciclib rechallenge has clinical benefits. Translational research to evaluate the gene alteration and immunohistochemistry will be conducted as an accompanying research to determine the predictive biomarkers of resistance or sensitivity to abemaciclib. Patients and Methods: The eligible patients are histologically confirmed with ER-positive and HER2-negative invasive breast cancer, locally advanced or metastatic, and previously received no more than two lines of endocrine therapy. The patients who previously received abemaciclib in combination with endocrine therapy led to a clinical benefit, including complete response, partial response, or stable disease, during abemaciclib-based treatment (≥6 months). The patients who previously received chemotherapy, immune checkpoint inhibitors (excluding perioperative systemic treatment), everolimus, olaparib, and palbociclib for advanced or metastatic diseases are excluded. The patients will be treated with abemaciclib 150 mg orally q12h on days 1 to 28 of a 28-day cycle. The other endocrine drug prescribed was not used in previous treatment. We will evaluate the gene mutations and/or amplification of ESR1, PIK3CA, CCNE1, FGFR1, RB1, TP53, NF1, MYC, AR, and MET at the time of inclusion and three months after day 1 and ctDNA and immunostaining levels of HER3, PTEN, CCNE1, FGFR1/2, and AR at the time of inclusion. The primary endpoint is progression-free survival (PFS), while the secondary endpoints are overall response rate, clinical benefit rate, chemotherapy-free interval, overall survival (OS), safety, and evaluation of the mechanism of sensitivity and resistance to abemaciclib. The expected median PFS for the study treatment arm is 5.0 months compared to the previous data of 3.0 months. The number of necessary cases is 59, with a significance level of 5% (two-sided) and power of 80% during the two-year recruitment period and one-year follow-up period. In the planned total of 65 cases, 10% is considered inappropriate. The planned duration of enrollment and follow-up is two years and one year, respectively. The planned total study duration is four years. Subgroup analysis will be performed on ESR1 and PIK3CA mutations, disease site (visceral/bone only/other), previous lines of therapy for advanced or metastatic disease (first and second), endocrine therapy for pretreatment (aromatase inhibitors/fuluvestrant), performance status (0/1), organs involved (1/2/≥3), age (<65/≥65 years), and disease-free interval (<36 months/≥36 months) to examine the interaction of treatment effects on PFS and OS. This study was funded by Eli Lilly and Company. Citation Format: Meiko Nishimura, Takahiro Kogawa, Yuko Akaishi, Misato Ogata, Jun Masuda, Mitsuo Terada, Hitomi Sakai, Kazuki Nozawa, Sasagu Kurozumi, Takamichi Yokoe, Yukinori Ozaki Ozaki, Shu Yazaki, Mai Onishi, Tsutomu Iwasa, Takuma Onoe, Yuta Okumura, Sayaka Nakayama, Kanako Hagio, Yuko Takahashi, Hirokazu Tanino, Junji Tsurutani, Koji Matsumoto, Mototsugu Shimokawa, Toshimi Takano. Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-02.

Abstract P3-14-12: Distinct and targetable molecular features of breast cancer in African American women

Abstract Introduction: Despite having a lower incidence of breast cancer, African American (AA) women suffer disproportionately worse outcomes; with more aggressive cancer and higher mortality rates, as well as higher incidence of triple negative breast cancer (TNBC). The cause of these disparities is unclear, but may be driven by different biologic and molecular features. Information about targetable molecular profiles for breast cancer in AAs is limited, and may not be representative of racial minorities. A better understanding of actionable targets is needed to improve treatment and outcomes of breast cancer for AA women. Materials and methods: This study utilized molecular data from three TCGA Breast Invasive Carcinoma studies (Cell 2015, Firehose Legacy, and PanCancer Atlas) on CBioPortal. Data was stratified by C/White and AA/Black to identify the most commonly affected genes, the most significantly differentially affected genes between the two populations, and 35 actionable genes. Genes were compared between racial subgroups (455 AA cases, 2103 C cases) for analysis of mutation types (point mutations, splice site, deletions, and amplifications) mutation load, overall survival, and mRNA expression vs. copy number variation (CNV). Data was assessed for differences, with p-value set at <0.05, and OncoPrints generated using tools in CBioPortal. Results: 2282 genes were differentially altered between white and black subgroups (P<0.05). Of the most commonly altered genes, only three were significantly different between AA and C: TP53, PIK3CA, and CSMD1 (p<0.001). PIK3CA missense mutations were more common in C (36.28% (C) vs 22.47% in AA). TP53 missense mutations were more prevalent in AA (40.09% vs. 28.58% in C). CSMD1 deletions, a tumor suppressor gene, were more prevalent in AA (19.78%) vs. 10.79% in C. We identified a cluster of genes at 8q24.21 (MYC, CASC8, POU51B, CCAT2) showing frequent co amplification in AA and C. For TNBC cases (18 AA cases, 52 C cases), the alteration rate of following genes was significantly between AA and C groups USF3 (27.8% in AA, 0% in C); PIK3C2B (27.8% AA, 1.9% C); SLC41A1 (27.8% AA, 3.85% C); PDHX, PRICKLE4, TOMM6 (all 27.8% AA, 5.8% C); and EHF and PRPF4B (both 27.8% AA, 7.7% C). Some of the genes with highest frequency in both groups include: TP53 (83.3% in AA, 78.9% C); PVT1 (38.9% AA, 46.2% C); CASC8, MYC, and POU51B (33.3% AA, 46.2% C). For actionable targets, PIK3CA, RAD51B, MSH6, KRAS, and NTRK3 were significantly different between AA and C (p<0.05). Of note, FGFR1 and NTRK1 amplifications were common in both AA and C subgroups, 17% AA/13% C and 15% AA/11% C respectively, and are potential targets for emerging therapeutics. Of note, TTN missense mutations were common in both subgroups (15.93% in AA and 18.11% in C), and may be an important marker of tumor mutational burden and predictive for immunotherapy responsiveness. ERBB2 was also commonly amplified in both groups (14% in AA and 12% in C). Survival analysis showed significantly worse outcomes for AA women with PIK3CA alterations (50% disease free for PIK3CA vs. 75% for unaltered at 75 months), while C women with PIK3CA alterations had improved outcomes (85% disease free for PIK3CA vs. 80% for unaltered at 75 months). Conclusion: Significant and diverse molecular differences exist in breast cancer between AA vs. C subgroups. Many of these molecular alterations are linked to specific treatment opportunities. The results indicate that comprehensive molecular profiling may have a major role in assessing treatments for patients with breast cancer, and that AA women may develop breast tumors with unique molecular features requiring novel treatment strategies. Citation Format: Genevra Magliocco, Roy Khalife, Anthony Magliocco. Distinct and targetable molecular features of breast cancer in African American women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-12.

Abstract PD6-07: Whole genome sequencing-based circulating tumor DNA profiling of metastatic breast cancer patients for molecular characterization and therapy response prediction

Abstract Background Previous studies proposed low-pass whole genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis as a versatile tool for genomic profiling and therapeutic monitoring of cancer patients. Here we demonstrate LP-WGS ctDNA genomic profiles and its clinical significance in metastatic breast cancer patients. Patients and methods This prospective exploratory study enrolled 207 treatment-naïve metastatic breast cancer patients from Feb 2017 to September 2020 in Yonsei Cancer Center. The median follow-up duration of patients was 35 months. The baseline (n=207) and post-progression (n=48) plasma samples were prospectively collected on first-line systemic therapy, and LP-WGS was employed for ctDNA somatic copy number alteration (CNA) analysis. The CNA burden of ctDNA was scored by “I-score” method, which was developed to measure genome-wide chromosomal instabilities, to be matched with therapy response. The unsupervised molecular clustering and homologous recombination deficiency (HRD) estimation by shallowHRD algorithm were performed using locus-level CNA profiles with 1 mega base pair resolution. Results The baseline I-score ctDNA CNA burden was highest in triple-negative breast cancer (TNBC) patients among subtypes, and the patients were dichotomized by median I-score level 5.54 (range 2.55 to 12.98). The high baseline ctDNA I-score was independently associated with poor overall survival (hazard ratio [HR] = 3.98, p < 0.001) with adjustment of tumor subtype, visceral metastasis, and disease status (de novo stage IV versus recurrent). The progression-free survival (PFS) on endocrine plus CDK4/6 inhibitors (HR = 2.75, p = 0.005), anti-HER2 therapy (HR = 2.52, p = 0.032), and cytotoxic chemotherapy (HR = 2.33, p = 0.012) was also shorter in high baseline I-score patients than in low I-score patients. The locus-level CNA profile was analyzed in high I-score patients (n=103), and the patients were classified into five molecular clusters with distinct overall survival by unsupervised k-means clustering of CNA profile: basal-like, EGFR-high basal-like, CCND1-high, luminal, and HER2-enriched clusters. Patients with BCL6 (p = 0.009) and PIK3CA amplification (p < 0.001) on baseline ctDNA showed significantly shorter PFS on CDK4/6 inhibitor treatment. The matched baseline and post-progression ctDNA analysis found emergence of FGFR1 amplification and MYC amplification after CDK4/6 inhibitor treatment (n=1, each). The ctDNA shallowHRD score was highest in TNBC patients among subtypes, and TNBC patients with high shallowHRD score (≥10) showed high response rate on (58.3% versus 28.6%) on platinum-based chemotherapy. Conclusion LP WGS-based ctDNA analysis provides a robust tool for non-invasive genomic clustering, therapy response prediction, and HRD estimation in metastatic breast cancer patients. All patients (n=207)Low I-score (n=104)High I-score (n=103)N (%)N (%)N (%)Age, Median (Interquartile range)54 (46-62)53 (47-60)54(44-62)GenderFemale205 (99)102 (98.1)103Male2 (1)2 (1.9)0SubtypeHR+ HER2-106 (51.2)61 (58.7)45 (43.7)HR- HER2+33 (15.9)14 (13.5)19 (18.4)HR+ HER2+22 (10.6)11 (10.6)11 (10.7)HR- HER2- (TNBC)46 (22.2)18 (17.3)28 (27.2)Disease statusDe novo stage IV74 (35.7)31 (29.8)43 (41.7)Recurrent133 (64.3)73 (70.2)60 (58.3)Primary therapyEndocrine + CDK 4/6 inhibitor97 (46.9)55 (52.9)42 (40.8)Anti-HER2 based therapy54 (26.1)24 (23.1)30 (29.1)Chemotherapy45 (21.7)16 (15.4)29 (28.2)Others11 (5.3)9 (8.7)2 (1.9)Visceral metastasisYes142 (68.6)60 (57.7)82 (79.6)No65 (31.4)44 (42.3)21 (20.4)Metastasis SitesLung89 (43)43 (41.3)46 (44.7)Brain19 (9.2)4 (3.8)15 (14.6)Liver59 (28.5)13 (12.5)46 (44.7)Bone120 (58)47 (45.2)73 (70.9)Lymph node90 (43.7)32 (30.8)58 (56.9)Pleura33 (15.9)17 (16.3)16 (15.5) Citation Format: Joohyuk Sohn, Min Hwan Kim, Jin Mo Ahn, Won-Ji Ryu, Seul-Gi Kim, Jee Hung Kim, Tae Yeong Kim, Hyun Ju Han, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Eun Hae Cho, Gun Min Kim. Whole genome sequencing-based circulating tumor DNA profiling of metastatic breast cancer patients for molecular characterization and therapy response prediction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-07.

FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort.

The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan-Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2-positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).

Efficacy of derazantinib in intrahepatic cholangiocarcinoma patients with FGFR2 mutations or amplifications: Interim results from the phase 2 study FIDES-01.

427 Background: Derazantinib, a potent anti- FGFR1-3 oral kinase inhibitor, has shown clinically meaningful anti-tumor activity (21%), durable responses (median, 6.4 months), and progression-free survival (median, 8.0 months) in patients (pts) with FGFR2 fusion (FGFR2F)-positive intrahepatic cholangiocarcinoma (iCCA), and with a manageable toxicity profile. Herein, we report an interim analysis of the clinical efficacy data of derazantinib for pts with iCCA harboring FGFR2 mutations or amplifications (FGFR2M/A), a potential therapeutic option currently not addressed by FGFR inhibitors. Methods: Study FIDES-01 enrolls in a dedicated cohort pts with FGFR2M/A+ advanced iCCA who received previous chemotherapy. Pts receive 300 mg derazantinib daily until disease progression, death or intolerance. The primary endpoint is the proportion of pts alive and free of disease progression at 3 months (PFS3; RECIST 1.1, central imaging review) using a Simon’s two-stage sample-size minimizing statistical design. The interim analysis population comprises 23 pts dosed (intention to treat) who had at least one post-baseline tumor assessment (or clinical progression, or died) by June 3, 2021, using investigator assessments based on RECIST 1.1. Results: To date, 28 pts have been enrolled and dosed. FGFR2M/A observed in these pts included missense point mutations (78%), other short variants (11%) and amplifications (11%). Transition from stage 1 to stage 2 of the study was achieved earlier than planned after 8 (67%) of 12 pts were assessed as PFS3 based on central imaging review. In 23 pts included in this interim analysis for efficacy, the best overall response (investigator assessment) was confirmed partial response in two (8.7%) and stable disease in additional 15 pts (65.2%), resulting in a disease control rate of 73.9% (95% CI, 51.6–89.8). Using Kaplan-Meier analyses, the median PFS was 7.3 months (95%CI, 3.5–16.7) and the probability of being progression-free at 3 months and at 6 months were 76.3% (95%CI, 51.9–89.4) and 50.3% (95%CI, 21.7–73.4), respectively. Clinically meaningful anti-tumor efficacy was observed across all types of genetic aberrations. The safety profile of derazantinib in FGFR2M/A+ iCCA pts was consistent with that previously reported for FGFR2F+ iCCA pts. Conclusions: This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment. Clinical trial information: NCT03230318.

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

HER2-positive breast cancer (BC) is an aggressive subtype that affects 20–25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC have dramatically improved since the introduction of anti-HER2 antibodies such as trastuzumab (TZ) and/or pertuzumab (PZ) added to chemotherapy. This study sought to examine whether correlation exists between copy number variations (CNVs) in several genes related to the PI3K/AKT pathway (HER2, FGFR1, PIK3CA, AKT3 and MDM2) and the efficacy of anti-HER2 neoadjuvant treatment in patients with early HER2-positive BC. Forty-nine patients received TZ or PZ/TZ and chemotherapy as neoadjuvant treatment. Gene CNVs were determined by quantitative polymerase chain reaction on paraffin-embedded biopsy specimens. The response to 6 months of therapy was assessed by Miller–Payne grading of the tumor on surgical resection; grades 4 and 5, indicating >90% tumor reduction, were defined as a good response. A good response was shown by 64.5% and a pCR by 31.2% of patients. When stratified by anti-HER2 antibody received and gene CNV, it was found that patients with FGFR1 gene amplification or those with FGFR1 amplification treated with TZ alone showed a poor response (p = 0.024 and p = 0.037, respectively). In the subset of patients treated with TZ/PZ combined, the pCR rate was significantly lower among those showing FGFR1 amplification (p = 0.021). Although based on a small sample size, our findings suggest that patients with FGFR1 amplification might benefit less from anti-HER2 antibody therapy.

High FGFR1-4 mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer.

FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively. Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence. High FGFR1-4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1-4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs. Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1-4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

P38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer.

FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.

HER2 Amplification by Next-Generation Sequencing in Lung Carcinoma: A Comparison of NGS Amplified and Non-amplified Cases by Immunohistochemistry and In Situ Hybridization

Background:Although the role of HER2 amplification and its evaluation methods are well known in breast carcinoma, methods for detection of HER2 amplification in non-small cell lung carcinoma are unclear. Next-generation sequencing is widely used in searching multiple therapeutic targets, and it is possible to evaluate copy number variation of genes by next-generation sequencing.Aims:To re-evaluate the HER2 status of non-small cell lung carcinoma cases detected as HER2 amplified and non-amplified by next-generation sequencing via the most commonly used HER2 investigation methods in routine pathology practice, namely immunohistochemistry and in situ hybridization.Study Design:Retrospective cross-sectional study.Methods:Among the 256 patients whose mutation profiles were examined by next-generation sequencing, HER2 amplified (13 cases) and non-HER2-amplified (13 cases) were determined as study and control groups, respectively, by next-generation sequencing. HER2 next-generation sequencing amplified tumors were investigated for HER2 expression and amplification using immunohistochemistry and silver in situ hybridization.Results:From a group of 256 non-small cell lung carcinoma, 33 tumors (12.8%) showed HER2 amplification with next-generation sequencing. Although we observed more frequent HER2 positivity by immunohistochemistry in next-generation sequencing-amplified cases, when compared to non-amplified cases (50% and 23% respectively), the difference was not significant (P = .221). Within the HER2 amplified group, inter-method-agreement was very good between next-generation sequencing results amplification and in situ hybridization status. Next-generation sequencing results showed a strong interclass correlation coefficient with HER2/cell (P = .009, r = 0.777) and HER2/CEP17 ratio (P = .001, r = 0.805). The median HER2/CEP17 ratio was higher in the next-generation sequencing amplified group (P = .013); however, three cases were found to be amplified by silver in situ hybridization among the next-generation sequencing non-amplified cases. EGFR and FGFR1 amplification were more frequent in HER2 next-generation sequencing amplified group than next-generation sequencing non-amplified group (P < .001).Conclusion:Until the effects of HER2 amplification on the HER2 protein are well understood and pulmonary carcinoma algorithms are defined, non-small cell lung carcinomas found to be amplified by next-generation sequencing should be verified by additional methods.

TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.

BackgroundWhereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer.MethodsIn this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each).ConclusionWe conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

INNV-08. LOW AND INTERMEDIATE GRADE GLIOMA UMBRELLA STUDY OF MOLECULAR GUIDED THERAPIES (LUMOS) STUDY

Abstract BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.

Predictive role of CCND1, FGFR1 gene amplifications and PIK3CA mutations for endocrine therapy of primary metastatic breast cancer

Background. More than half of breast carcinomas express estrogen and progesterone receptors (ER and PR) and remain estrogen-dependent. Endocrine therapy with inhibitors of the estrogen cascade allows long-term and effective control of the disease in a significant number of patients, however, some patients demonstrate primary, and the majority - secondary resistance to such treatment.&#x0D; The aim of the study was to evaluate the predictive significance of the CCND1 and FGFR1 gene amplifications and PIK3CA mutations for endocrine therapy.&#x0D; Materials and methods. The study included 138 women with ER-positive primary metastatic breast cancer (BC) who received hormone therapy with aromatase inhibitors (AIs) (n = 69), tamoxifen (n = 65), goserelin (n = 2), or a combination of goserelin and tamoxifen (n = 2) as the first line treatment. CCND1 and FGFR1 gene amplifications were tested by digital droplet PCR, while mutations in exons 7, 9, and 20 of the PIK3CA gene were determined using high-resolution melting analysis and allele-specific PCR. We analyzed the associations between the presence of the mentioned genetic lesions, progression-free-survival (PFS) and response to treatment.&#x0D; Results. Amplifications of CCND1 and FGFR1 genes were identified in 24 (17.9%) and 28 (20.9%) of 134 successfully tested cases, respectively; 9 tumors were positive for both alterations. Amplifications were more prevalent in less differentiated tumors (p = 0.018). CCND1 amplification was associated with shorter PFS in patients receiving aromatase inhibitors (16.0 months vs. 32.4 months, HR = 3.16 [95% CI: 1.26-7.93], p = 0.014). FGFR1 status did not significantly affect PFS of AI-treated women, however, partial regress as a result of AI implementation was less frequent in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number (p = 0.031).&#x0D; The frequency of PIK3CA mutations was 40.2% (49/122). They were more often observed in smaller tumors (p = 0.034), in PR-positive carcinomas (p = 0.012), and in cases with more extensive metastatic involvement (p = 0.029). The presence of PIK3CA mutations did not affect the results of treatment with AI or tamoxifen.&#x0D; Conclusion The presence of CCND1 and/or FGFR1 amplification is associated with worse results of AI therapy of metastatic breast cancer.

P71.03 A New Combination Therapy for FGFR1-Amplified Lung Cancer

FGFR signaling is frequently deregulated in cancers. Compelling evidence has demonstrated the oncogenic potential of deregulated FGFR signaling in driving tumor growth. In particular, FGFR1 amplifications occur in 10–20% of lung cancer, primarily squamous cell lung carcinoma (SQLC), making FGFR1 the biggest class of