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Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention.Significance:The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.

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Aim: To describe the overall cancer-related healthcare utilization patterns, treatment patterns and outcomes in women diagnosed with platinum-sensitive recurrent high-grade serous ovarian cancer. Patients & methods: Subanalysis of the Spanish sample of a retrospective, noninterventional, multinational, observational study. Results: BRCA -mutated patients had better outcomes in terms of progression-free survival and overall survival than patients who were BRCA wild-type. It was observed that patients’ treatment outcomes after the first recurrence progressively worsened as the patient underwent subsequent chemotherapy lines. Healthcare resource utilization when accounting for the follow-up time did not substantially differ between BRCA1 / 2 -mutated and BRCA wild-type patients. Conclusion: BRCA1/2 mutation carriers have better treatment outcomes, including longer survival, without a negative impact on the use of healthcare resources.

Background: HER2 overexpression is an established molecular target in breast and gastric cancer therapy, but no HER2-targeted therapies are currently available for NSCLC. In studies of NSCLC and lung cancer overall, the prevalence of HER2 overexpression has been reported to be anywhere from Methods: DESTINY-Lung03 (NCT04686305) is a phase 1b, open-label, multicenter, dose-escalation (part 1) and dose-expansion (part 2) study in pts with HER2-overexpressing (≥25% immunohistochemistry 2+/3+ tumor cells), unresectable, locally advanced or metastatic, nonsquamous NSCLC. In part 1, pts with progression after 1 or 2 lines of systemic therapy in the recurrent/metastatic setting are enrolled to receive T-DXd and durvalumab in combination with cisplatin (arm 1A), carboplatin (arm 1B), or pemetrexed (arm 1C), or T-DXd monotherapy (arm 1D). In part 2, pts who have not received prior curative treatment in the locally advanced setting or systemic treatment in the metastatic setting are enrolled to receive T-DXd and durvalumab in combination with cisplatin (arm 2A), carboplatin (arm 2B), or pemetrexed (arm 2C), or T-DXd plus durvalumab (arm 2D); pts in part 2 must not have activating EGFR mutations, an EML4-ALK fusion, or other targetable alterations. The primary endpoint is the frequency of adverse events (AEs) and serious AEs (SAEs) with T-DXd plus durvalumab plus chemotherapy combinations to assess safety and tolerability and determine the recommended phase 2 dose. Secondary endpoints include confirmed ORR, duration of response, disease control rate, progression-free survival, OS, frequency of AEs and SAEs with T-DXd monotherapy (part 1) and T-DXd plus durvalumab (part 2), pharmacokinetics, and immunogenicity. Citation Format: David Planchard, Julie R. Brahmer, James C. Yang, Yuh-Min Chen, Kang-Yun Lee, Thatthan Suksombooncharoen, Natasha Viglianti, Mark Gustavson, Alejandra Ragone, Amaya Gasco Hernandez. Phase 1b dose-escalation and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd) in combination with durvalumab and cisplatin, carboplatin, or pemetrexed in advanced or metastatic, HER2-overexpressing, nonsquamous non-small cell lung cancer (NSCLC): DESTINY-Lung03 [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 CT572.

TPS9137 Background: The standard of care (SOC) for patients with oncogene driver subsets of metastatic NSCLC is guided by specific molecular characterization and includes immunotherapy, chemoimmunotherapy, and matched targeted therapies. Although targeting HER2 has transformed the care of patients with breast and gastric cancers, there is currently no approved HER2-targeted therapy for NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients (median, 2 prior lines) with unresectable or metastatic HER2-mutant NSCLC, T-DXd demonstrated durable and robust anticancer activity, with a confirmed objective response rate (ORR) of 55% and median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of 9.3, 8.2, and 17.8 months, respectively (Li et al. N Engl J Med. 2022). Given the efficacy observed in later-line settings and the unmet need for targeted therapies in patients with HER2-mutant NSCLC, evaluating the efficacy of T-DXd in the first-line setting vs SOC is important to determine the optimal treatment. Here we describe the phase 3 DESTINY-Lung04 trial (NCT05048797) evaluating T-DXd as a first-line treatment in patients with NSCLC harboring HER2 mutations. Methods: DESTINY-Lung04 is an open-label, randomized, multicenter, phase 3 study evaluating the efficacy and safety of first-line T-DXd vs SOC in patients with unresectable, locally advanced (not amenable to curative therapy), or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations (detected in tissue or circulating tumor DNA). Patients must be naive to systemic therapy with palliative intent in the locally advanced or metastatic disease setting and must not have tumors with EGFR or other targetable oncogenic alterations. Patients with brain metastases must have previously completed local therapy. Patients will be randomized to receive T-DXd or SOC (platinum [investigator’s choice of cisplatin or carboplatin], pemetrexed, and pembrolizumab). The primary endpoint is PFS defined by RECIST version 1.1 per blinded independent central review (BICR). Secondary endpoints include OS, ORR, and DOR (by RECIST 1.1 per BICR and investigator), investigator-assessed PFS (by RECIST 1.1) and time to second progression or death (per local standard clinical practice), central nervous system PFS (by RECIST 1.1 per BICR), landmark PFS at 12 months (by RECIST 1.1 per BICR and investigator), and landmark OS at 24 months. Safety and tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes, including pulmonary symptoms and tolerability, will be assessed. Clinical trial information: NCT05048797.

Non-small-cell lung cancer (NSCLC) is a disseminated disease in 50% of cases, with a gloomy prognosis and median survivals of1 year.Based on substantial advances, cancer biology insights and novel biotechnology tools, customized treatment provides hints that cisplatin-based treatment can be optimized in favorable subgroups of patients according to gene expression DNA repair profiles. In 2004, it was discovered that 10-15% of NSCLC can harbor a new class of EGFR mutation conferring specific sensitivity to EGFR tyrosine kinase inhibitors.The homologous recombination pathway provides information for customizing cisplatin-based chemotherapy. BRCA1 plays a central role in this pathway that can be used in tailoring chemotherapy. Patient subgroups can obtain significant increases in progression-free survival. For EGFR lung-addicted cancers, treatment with EGFR tyrosine kinase inhibitors like erlotinib provide impressive improvement in progression-free survival--up to 14 months with significant enhanced survival.Customized chemotherapy based on BRCA1 models can contribute to demonstrating this approach's clinical relevance, and the implementation of EGFR mutation assessment is warranted to identify EGFR-addicted lung cancers with a different prognosis that could benefit from a specifically targeted therapy approach.

Introduction Lung adenocarcinoma patients harboring EGFR activating mutations attain improved progression-free survival (PFS) with treatment with epidermal growth factor receptor tyrosine kinase inhibitors. However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways. Methods We examined the mRNA expression of C terminus-binding protein–interacting protein and Lin11 , Isl-1 , and Mec-3 domain only 4 ( LMO4 ) in pretreatment tumor samples from 91 erlotinib-treated advanced non–small-cell lung cancer patients with EGFR mutations in whom breast cancer gene 1 ( BRCA1 ) expression and the concomitant presence of the EGFR T790M mutation had previously been assessed. Gene expression was analyzed by polymerase chain reaction, using β-actin as endogenous gene. Results were correlated with PFS and overall survival. Results In patients with low LMO4 levels, PFS was 13 months, whereas it was not reached for those with high LMO4 levels ( p = 0.03). In patients with low levels of both BRCA1 and LMO4 , PFS was 19 months whereas it was not reached in those with low BRCA1 and high LMO4 mRNA levels ( p = 0.04). In patients with high BRCA1 and low LMO4 levels, PFS was 8 months, whereas it was 18 months in those with high levels of both genes ( p = 0.03). Conclusions Low BRCA1 and high LMO4 levels were associated with longer PFS to erlotinib. Baseline assessment of BRCA1 and LMO4 mRNA expression can help predict outcome to erlotinib.

It is widely acknowledged that there is a need for molecular profiling in non-small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a MEK inhibitor and in BRAF(V600E) melanoma cell lines treated with BRAF inhibitors. This rebound effect of overexpression of several RTKs, including ERBB3, also occurs in lung cancers driven by Kras or EGFR mutations when treated with MEK, PI3K or dual PI3K/mTOR inhibitors. Synthetic lethality can be effectively induced by co-targeting these overexpressed RTKs. We speculate that in patients with EGFR mutations, adaptive resistance occurs in a significant proportion of patients. Rebiopsies performed hours after starting treatment with EGFR TKIs can identify which RTKs are overexpressed after treatment. Efficient co-targeting of these RTKs can induce synthetic lethality and help overcome the limited effect of EGFR TKI monotherapy.

7542 Background: Rash is reported in 75% of p treated with erlotinib and has been associated with improved overall and progression-free survival (PFS) in unselected p although not specifically in p with EGFR mutations. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m, respectively (P

Background Metastatic non-small-cell lung cancer (NSCLC) has a dismal prognosis. EGFR is overexpressed or mutated in a large proportion of cases. Downstream components of the EGFR pathway and crosstalk with the NF-κB pathway have not been examined at the clinical level. We explored the prognostic significance of the mRNA expression of nine genes in the EGFR and NF-κB pathways and of BRCA1 and RAP80 in patients in whom EGFR and K-ras gene status had previously been determined. In addition, NFKBIA and DUSP22 gene status was also determined. Methods mRNA expression of the eleven genes was determined by QPCR in 60 metastatic NSCLC patients and in nine lung cancer cell lines. Exon 3 of NFKBIA and exon 6 of DUSP22 were analyzed by direct sequencing. Results were correlated with outcome to platinum-based chemotherapy in patients with wild-type EGFR and to erlotinib in those with EGFR mutations. Results BRCA1 mRNA expression was correlated with EZH2, AEG-1, Musashi-2, CYLD and TRAF6 expression. In patients with low levels of both BRCA1 and AEG-1, PFS was 13.02 months, compared to 5.4 months in those with high levels of both genes and 7.7 months for those with other combinations (P = 0.025). The multivariate analysis for PFS confirmed the prognostic role of high BRCA1/AEG-1 expression (HR, 3.1; P = 0.01). Neither NFKBIA nor DUSP22 mutations were found in any of the tumour samples or cell lines. Conclusions The present study provides a better understanding of the behaviour of metastatic NSCLC and identifies the combination of BRCA1 and AEG-1 expression as a potential prognostic model.

11025 Background: SOX2 is a key transcription factor that is amplified in lung SCC. FGFR1 is a receptor tyrosine kinase that promotes cell proliferation, survival and apoptotic resistance through the PLCγ/PKC, RAS/MAPK and PI3K-AKT pathways, respectively. FGFR1 is amplified in 15-25% of lung SCC. Pre-clinical studies of targeted inhibitors showed a growth dependency on FGFR1 amplification both in vitro and in vivo. A European, multicenter clinical trial of second-line treatment with BIBF1120, an FGFR1 inhibitor, will be performed in p with lung SCC with FGFR1 amplification. Methods: We have examined FGFR1 and SOX2 gene copy number (GCN) in 76 lung SCC p by multiplex ligation-dependent probe amplification (MLPA). Genomic DNA (gDNA) was isolated from enriched tumor cells by laser capture microdissection from formalin-fixed paraffin embedded (FFPE) tumor tissue. 50-100 ng of gDNA was analyzed in each of three independent replicates per tumor sample. Two independent probe sets were used for each gene analyzed. For inter-patient GCN comparisons, the results from each patient were normalized against the GCN values derived from FFPE peripheral blood leukocytes. In order to study intra-tumor heterogeneity (TH), we examined FGFR1 and SOX2 GCN in different areas of 4 tumors. In 2 p, TH was examined in serial tumor biopsies and/or resections obtained at different points of disease progression. Results: High FGFR1 amplification was detected in 13/76 (17.10%) and low amplification in 7/76 (9.21%) p. High SOX2 amplification was observed in 38/63 (60.32%) and low amplification in 9/63 (14.28%) p. 46.15% of the FGFR1-amplified tumors were also co-amplified for SOX2. Intra-TH was observed in 2/4 tumors. Survival according to FGFR1 and SOX2 GCN will be presented. In addition, GCN changes in FGFR1, SOX2, PIK3CA, PDGFRA, KDR, EGFR and MET over 10 years of follow-up will be presented for one surgically resected SCC lung p. Conclusions: FGFR1 and SOX2 co-amplification could represent a novel therapeutic target and warrants further research.

11029 Background: The tumor suppressor TP53 is the most commonly mutated gene in lung cancer. Early-stage NSCLC p with TP53 mutations may have worse prognosis and be more radio/chemoresistant. However, few studies have addressed the issue of TP53 mutations in advanced NSCLC. We have retrospectively examined the influence of TP53 mutations on OS in 241 advanced NSCLC p. Methods: 99 EGFR-wild-type (wt), chemotherapy-treated p from 5 European hospitals and 142 EGFR-mutated (mut), erlotinib-treated p from two clinical studies were included. Exons 5, 6, 7 and 8 of TP53were analyzed by high resolution melting (HRM). All mutated samples were reconfirmed by sequencing. Mutations were classified as disruptive or non-disruptive based on their predicted effects on the function of the p53 protein. Results: TP53 mutations were detected in 31% of EGFR-wt and 24% of EGFR-mut p. OS results are available for 57 EGFR-wt p and 90 EGFR-mut p. Among EGFR-wt p, OS was 22 months (m) for p without TP53 mutations, 20m for p with disruptive TP53 mutations, and 9 m for p with non-disruptive TP53 mutations (P=0.09). Among EGFR-mut p, OS was 31 m for p without TP53 mutations, not reached for p with disruptive TP53 mutations, and 15 m for p with non-disruptive TP53 mutations (P=0.05). Complete OS results for all 241 p will be presented. Conclusions: Non-disruptive mutations in the TP53 gene are associated with shorter OS in advanced NSCLC p, both in EGFR-wt p treated with chemotherapy and in EGFR-mut p treated with erlotinib.These p could benefit from treatment to reactivate mutant p53.

e22119 Background: Although it is know that pCR following neoadjuvant chemotherapy is more frequent in some subtypes of breast cancer such as Triple Negative (TN) or erb2 tumors, the predictive role of gene expression and mutation status is not well defined in this setting. Methods: We analyzed samples from 41 patients (p) prospectively treated with neoadjuvant chemotherapy (sequential AC followed by weekly TXL, or inverse sequence, plus trastuzumab for erb2 positive p). Pathologic response (PR) was classified according to Miller-Payne and RCB criteria. Radiologic evaluation was performed by ultrasonography, dynamic MR and PET-TAC after each chemotherapy sequence. We performed expression analysis of AXL, BRCA1, RAP80, BIM, EZH2, ROR1, FGFR1, PTPN12, YAP, GAS6, beta-TRCP, HIF1 alpha and ZNF217 by RT-PCR, and mutational status of p53 and PI3K genes in pretreatment biopsies. Statistical analysis was performed using Mann-Whitney U and Pearson’s chi-squared tests. Results: pCR was detected in 5 p (3TN, 2 erb2) of 25 p (9 luminal A, 5 luminal B, 6 erb2 and 5 TN) evaluated for PR at time of submitting this abstract. TN tumors had lower levels of RAP80 (p=.0013), PTPN12 (p=.003), beta TRCP (p=.001), ZNF217 (p=.014) and YAP (p=.097). Luminal B tumors had low levels of YAP and the highest levels of FGFR1 (p=.09) and ZNF217 (p=.014). Luminal A tumors had high levels of beta-TRCP (p=.003). We found no differences in BRCA1, AXL, BIM, EZH2, ROR1, GAS6 and HIF1 levels by breast cancer subtype. P with low levels of FGFR1 (p=.087), HIF1alpha (p=.07) or EZH2 (p=.005) had higher probability of pCR. No pCR was observed in p with higher levels of AXL, EZH2, RAP80, GAS6, beta TRCP, HIF alpha. Four p had p53 mutations (1 luminal B, 1 erb2 and 2 TN) and 4 p had PI3K mutations (2 luminal A, 1 erb2, 1 luminal B). There was no correlation between p53 status and PR. P with PI3K mutations did not achieve pCR vs 46% of p with wild type PI3K (p=.23). Conclusions: Gene expression profile varies by breast cancer subtype. Chemosensitivity could be higher in tumors with lower levels of FGFR1, HIF1alpha or EZH2. Further results will be presented.

SRY-related HMG-box (SOX2) gene is a key transcription factor that coordinates development, differentiation and self-renewal of normal non-alveolar epithelium of the airway. SOX2 amplification has been reported in lung squamous cell carcinoma (SCC). Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase that, upon activation, promotes cell proliferation, survival and apoptotic resistance through PLCγ/PKC, RAS/MAPK and PI3K-AKT pathways, respectively. FGFR1 is also amplified in 15-25% of lung SCC and pre-clinical data with targeted inhibitors showed a growth dependency on FGFR1 amplification either in vitro and in vivo. A clinical trial with BIBF1120 (which also inhibits FGFR1), will be developed in the Netherlands and Spain in second line SCC of the lung with FGFR1 amplified by FISH. Genetic heterogeneity in solid tumors is a major research area and therefore its assessment in SCC of the lung is of great relevance. We have examined FGFR1 and SOX2 gene copy number (GCN) in 76 lung SCC by multiplex ligation-dependent probe amplification (MLPA). Analysis of mutations in DDR2, PIK3CA, BRAF, EGFR, KRAS, and TP53 is ongoing. Genomic DNA (gDNA) was isolated from enriched tumor cells by laser captured microdisection from formalin-fixed paraffin embedded (FFPE) tumor tissue sections. 50-100 ng of gDNA was analyzed in each of the three independent replicates per tumor sample. Two independent probe sets were used for each gene analyzed. For inter-patient GCN value comparisons, the tumor results from each patient was normalized against the GCN values derived from FFPE peripheral blood leukocytes control. We also used MLPA technique to study intra-tumor heterogeneity (TH) by analyzing FGFR1 and SOX2 in different tumor areas. In particular, in 4 cases FGFR1 and SOX2 were co-amplified. Also, TH was examined in serial tumor biopsies and/or resections obtained at different points of disease progression in two patients. Of the 76 patients evaluable for FGFR1 and SOX2 GCN, FGFR1 high amplification was detected in 13/76 (17.10%) and low amplification in 7/76 (9.21%). SOX2 presented high amplification in 38/63 (60.32%) and low amplification in 9/63 (14.28%). Interestingly, 46.15% of the FGFR1-amplified tumors were also co-amplified for SOX2. An important degree of TH was found in 2 of the 4 tumors analyzed. GCN changes in FGFR1, SOX2, PIK3CA, PDGFRa, KDR, EGFR and MET over 10 years follow-up will be presented for one surgically resected SCC lung cancer patient. Frequencies of FGFR1 and SOX2 gene amplifications detected are in agreement with previously published data. Survival according to FGFR1 and SOX2 status will also be presented. FGFR1 and SOX2 co-amplification, together with the TH, warrants further research and could represent a novel therapeutic target. Citation Format: Pedro Méndez, José L. Ramirez, Amaya Gascó, Teresa Morán, Enric Carcereny, Miquel Taron, José Luís Mate, Irene Sansano, María Pérez, Mónica Botia, Montserrat Tierno, Harry J.M Groen, Rafael Rosell. FGFR1 and SOX2 amplification in squamous cell carcinoma (SCC) of the lung. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 53. doi:10.1158/1538-7445.AM2013-53

Background High BRCA1 mRNA levels affected progression-free survival (PFS) to erlotinib in EGFR-mutant NSCLC p (Rosell et al. CCR 2011). LMO4 is a negative regulator of BRCA1 function, and CtIP can bind to BRCA1 and LMO4. We have assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP and LMO4 levels on outcome. Methods mRNA expression of BRCA1, LMO4 and CtIP was examined by RT-PCR in the original pretreatment tumor biopsies of 72 erlotinb-treated NSCLC p with sensitive EGFR mutations. Results p characteristics: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% never-smokers; 81.8% ECOG PS Conclusions Low BRCA1 and high LMO4 levels were associated with longer PFS in erlotinib-treated advanced NSCLC p with EGFR mutations. We recommend baseline assessment of BRCA1 and LMO4 mRNA expression to predict outcome and provide alternative individualized treatment to patients when indicated. HR 95%CI P BRCA1 ≤4.92 1 ref. 4.92-10.7 5.32 1.45-19.52 0.03 >10.7 5.13 1.25-20.99 0.02 CtIP ≤1.21 1 ref. 1.21-2.1 0.69 0.24-2.02 0.50 >2.1 1.10 0.42-2.89 0.84 LMO4 ≤1.29 6.02 1.51-23.94 0.01 1.29-1.86 2.81 0.85-9.21 0.09 >1.86 1 ref. Disclosure All authors have declared no conflicts of interest.

e18137 Background: Advanced NSCLC p with EGFR activating mutations show an impressive progression-free survival (PFS) to erlotinib. The co-existence of the EGFR T790M mutation, in conjunction with high BRCA1 mRNA levels, affected PFS to erlotinib (Rosell et al. CCR 2011). LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers, and CtIP can bind to BRCA1 and LMO4. We have assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP and LMO4 levels on outcome. Methods: mRNA expression of LMO4 and CtIP was examined by RT-PCR in the original pretreatment tumor biopsies of 81 NSCLC p with sensitive EGFR mutations. Results: Expression of BRCA1 and LMO4 was successfully assessed in 55 p: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% never-smokers; 81.8% ECOG PS

e18143 Background: Advanced NSCLC p with EGFR mutations have a median PFS of 14 months (m) and OS of 27 m when treated with erlotinib. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent upregulation of Fas and caspase activation leading to apoptosis, but this mechanism was defective in p53-null cells. We tested whether TP53 mutations influence outcome to erlotinib in EGFR-mutated p. Expression levels of the p53 repressor MDM2 were also examined. Methods: We assessed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR-mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis followed by sequencing of the amplified products with non-wild-type (wt) melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of TP53 were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations were less frequent in p with ECOG PS >2 and more frequent in p with the T790M mutation. OS was 15 m in the 16 p with missense mutations 31 m in p with wt p53 and not reached in p with non-missense mutations (P=0.04). PFS was 9 m for 14 p with mutations in one of the p53 DNA binding motifs (DBMs), compared to 19 m for wt p and 27 m for p with non-DBM mutations. MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially in DBM mutations. In the case of wt p, high MDM2 expression correlated with longer PFS and OS in p with wt p53. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; missense mutations correlate with shorter OS and mutations in DBMs correlate with shorter PFS. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring certain types of mutations in the TP53 gene.

Background Advanced NSCLC p harboring EGFR mutations show impressive progression-free survival (PFS) when treated with erlotinib. However, presence of EGFR mutations only imperfectly predicts outcome. We demonstrated that co-existence of the EGFR T790M pretreatment mutation was detected in one-third of p and, in conjunction with elevated BRCA1 mRNA levels, dramatically influenced PFS to erlotinib. Though this model is a breakthrough in outcome of EGFR-mutated NSCLC p treated with TKIs, we choose to analyze the impact of CTIP and LMO4 gene expression levels on p outcome and their correlation with BRCA1. CtIP binds to BRCA1 and LMO4 forming a complex. LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers. Methods mRNA expression of LMO4 and CTIP was examined by RT-PCR in pretreatment tumor biopsies of 72 NSCLC p with EGFR mutations treated with erlotinib. Expression levels were correlated with outcome to erlotinib and BRCA1 expression levels. Results BRCA1 significantly correlated with CtIP (r=0.31;P=0.01) and LMO4 (r=0.32;P=0.02). There was no correlation between CtIP and LMO4 (r=0.09;P=0.49).PFS was not reached for p with high levels of LMO4 vs 13 months for p with low levels (P=0.006). Overall survival (OS) was not reached for p with high levels of LMO4 vs 29 months for p with low levels (P=0.10). Expression levels of CtIP did not correlate with PFS and OS. PFS was not reached for p with low levels of BRCA1 and high levels of LMO4 vs 19 months for p with low levels of both genes (P=0.04). PFS was 8 months for p with high levels of BRCA1 and low levels of LMO4 vs 18 months for p with high levels of both genes (P=0.03). Conclusions BRCA1 and LMO4 mRNA levels examined by RT-PCR could predict PFS to erlotinib in p with EGFR mutations and could be useful for development of new therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1727. doi:1538-7445.AM2012-1727

e21025 Background: Genetic diversity in lung cancer according to histological subtype has not been fully explored. BRCA1 and RAP80 influence response to chemotherapy. Musashi 2 activates HES-1 in t...

10541 Background: NSCLC p with EGFR mutations respond to the oral EGFR tyrosine kinase inhibitors erlotinib and gefitinib, although the duration of response in individual p is unpredictable. In our...

7586 Background: Little is known about the potential effect of genetic alterations in the NFkB and Notch pathways on NSCLC p. Musashi 2 activates HES-1 in the Notch pathway, and HES-1 can abrogate ...

Background: Low BRCA1 mRNA expression significantly prolongs progression-free survival (PFS) to erlotinib in EGFR-mutant NSCLC patients (p). In order to explore other genes potentially involved in erlotinib resistance, we used NanoString, an integrated digital technology, to examine expression levels of 48 genes in a single reaction. Several genes involved in homologous recombination repair were included in the 48-gene assessment, including the E3 ubiquitin ligases RNF8, RNF168 and RAP80. Methods: CodeSets (Reporter and Capture probe sets) for 48 genes were custom-designed by NanoString Technologies. 100ng of total RNA for each sample was mixed with the reagents and hybridized at 65° overnight. Samples were processed and analyzed with the nCounter Prep Station (NanoString Technologies). Data analysis was performed adjusting the expression values according to positive control values and normalizing the data according to housekeeping genes. Results: In 43 EGFR-mutant NSCLC p treated with erlotinib, response rate was 67.6%, PFS was 16 months (m), median survival (MS) was 29 m. Three genes were significantly associated with PFS: PIAS1, DBC1 and AEG-1. Median PFS was not reached in p with low levels of AEG-1, while it was 18 m for p with intermediate levels and 5 m for p with high levels (P=0.002). In the multivariate analysis, the hazard ratio for high levels of AEG-1 was 14 (P Conclusions: AEG-1 activates the NF-κB and PI3K/Akt pathways, induces the transcription factor LSF, which upregulates TS, ALDH3A1 and Met, conferring resistance to several cytotoxic drugs. AEG-1 mRNA expression predicts outcome to erlotinib-treated EGFR-mutant NSCLC p and could have important implications for the optimal management of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2011-4110

7549 Background: In-frame deletions of exon 19 n est around the LREA string of amino acids (aa) located between residu es 747-750 of the EGFR polypeptide. Although outcome to erlotinib has been ass...

7540 Background: Different exon 19 deletion types have shown different in vitro sensitivity to erlotinib, with the lower IC50 for deletion E746_A750 (ELREA) (Yuza et al. Cancer Biol Ther 2007). This information prompted us to examine outcome according to type of exon 19 deletion in the EURTAC study. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P