Worst Progression-free Survival Research Articles

Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma.

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1months, and the median overall survival (OS) was 7.1months. The failure group, which was characterized by Deaville score (DS) 3-4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected) and low-risk groups (DS 1-2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1-2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

Identification of DNA methylation characteristics associated with metastasis and prognosis in colorectal cancer

Colorectal cancer (CRC) is prone to metastasis and recurrence after surgery, which is one of the main causes for its poor treatment and prognosis. Therefore, it is essential to identify biomarkers associated with metastasis and recurrence in CRC. DNA methylation has a regulatory role in cancer metastasis, tumor immune microenvironment (TME), and prognosis and may be one of the most valuable biomarkers for predicting CRC metastasis and prognosis. We constructed a diagnostic model and nomogram that can effectively predict CRC metastasis based on the differential methylation CpG sites (DMCs) between metastatic and non-metastatic CRC patients. Then, we identified 17 DMCs associated with progression free survival (PFS) of CRC and constructed a prognostic model. The prognosis model based on 17 DMCs can predict the PFS of CRC with medium to high accuracy. The results of immunohistochemical analysis indicated that the protein expression levels of the genes involved in prognostic DMCs were different between normal and colorectal cancer tissues. According to the results of immune-related analysis, we found that the low-risk patients had better immunotherapy response. In addition, high risk scores were negatively correlated with high tumor mutation burden (TMB) levels, and patients with low TMB levels in the high-risk group had the worst PFS. Our work shows the clinical value of DNA methylation in predicting CRC metastasis and PFS, as well as their correlation with TME, immunotherapy, and TMB, which helps understand the changes of DNA methylation in CRC metastasis and improving the treatment and prognosis of CRC.

Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study

BackgroundImmune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy.Patients and MethodsMedical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors.ResultsIn total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1–2 or 3–4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001).ConclusionsOur study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

Anatomical assessment of local recurrence site in breast cancer patients after breast reconstruction and post-mastectomy radiotherapy: implications for radiation volumes and techniques.

Post-mastectomy radiotherapy (PMRT) improves local control rates and survival in patients with adverse prognostic features. The dose coverage to target volumes is critical to yield maximum benefit to treated patients, increasing local control and reducing risk of toxicity. This study aims to assess patterns of breast cancer relapse in patients treated with mastectomy, breast reconstruction and PMRT. Breast cancer patients treated with PMRT between 1992 and 2017 were retrospectively reviewed. Clinical and pathological characteristics of patients were collected. Recurrences were defined as "in field," "marginal" or "out of field." Survival analyses were performed in relation to progression-free survival (PFS) and overall survival (OS). Correlation between baseline features was explored. Data of 140 patients are collected. After a median follow-up time of 72 months, median PFS and OS of 63 and 74 months were detected, respectively. Neoadjuvant chemotherapy, lympho-vascular space invasion (LVI) and size of primary tumor were all significantly associated with worst PFS and OS. Ten patients developed local recurrence: 30% "in field," 30% marginal recurrences, 20% "out of field" and 20% both "in field" and "out of field." No recurrence was detected under the expander, 80% above the device and 20% patients relapsed on IMN chain. The mean distant relapse-free survival was 39 months. Overall, 39 of 140 patients developed distant metastases. The onset of local-regional relapses occurred mainly above the expander/prosthesis, underlying the importance of inclusion of the subcutaneous tissues within the target volume. In order to refine new contouring recommendations for PMRT and breast reconstruction, future prospective studies are needed.

Abstract B031: High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes

Abstract Introduction: Recent publications have identified ‘low risk’ (LR-NSMP) and ‘high risk’ no specific molecular profile (HR-NSMP) endometrial cancers (ECs). Although LR-NSMP (low grade (G1/2) estrogen receptor (ER) positive tumors have extremely low rates (&amp;lt;2%) of death from disease and are considered candidates for de-escalation of adjuvant therapy, little is known about the newly defined entity of HR-NSMP (G3 and/or ER-negative), including optimal management, with 27% of HR-NSMP patients dying from their disease We aimed to perform in-depth characterization of a cohort of HR-NSMP ECs to identify additional prognostic or predictive features that may inform management. Methods: Clinicopathologic data collection, immunohistochemistry (IHC), and next generation sequencing was performed on a cohort of 148 HR-NSMP ECs testing for associations with outcomes. Three subgroups of HR-NSMP were assessed: i) low grade without any ER expression (G1/2ER-, n=40), ii) high grade with ER (G3ER+, n=67), and iii) high grade without ER expression (G3ER-, n=41). Results: In a univariate analysis, advanced stage (III/IV), positive lymph node (LN) status, no LN assessment, and PIK3CA mutations were associated with inferior progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS). HR-NSMP patients with positive LNs had a hazard ratio (HR) of death of 7.55 (95% CI: 3.41−16.73) compared to node negative. Additionally, patients with no LN assessment had an increased risk of death with a HR of 2.33 (95% CI: 1.12−4.85) compared to node negative. Within the three HR-NSMP subgroups, the worst OS (HR 7.06, CI 4.12-12.09, p&amp;lt; 0.001), DSS (HR 20.43, CI 10.14-41.19, p&amp;lt; 0.001), and PFS (HR 3.69, CI 1.59-8.63, p&amp;lt;0.001) were observed in patients with both adverse features (G3ER-). PIK3CA mutations were found in 32.7% of all HR-NSMP tumors tested (G1/2ER- 45.5%, G3ER+ 42.3%, G3ER- 6.7%) and associated with inferior OS (HR 4.84, CI 1.21-19.41, p=0.014), DSS (HR 4.84, CI 1.21-19.41, p=0.014), and PFS (HR 3.22, CI=1.08-9.66, p=0.028). There was a trend towards decreased OS and DSS in HR-NSMP patients with overexpression of HER2 IHC. L1CAM IHC overexpression and CTNNB1 mutation status were not associated with outcomes when assessed across all HR-NSMP or within subgroups. Conclusion: Among HR-NSMP ECs, the worst clinical outcomes were observed in patients harboring both high grade and ER negative tumors. In contrast to LR-NSMP ECs where patients who had no lymph node assessment had excellent outcomes mirroring node negative status, HR-NSMP patients who had no nodal assessment had a high rate of recurrence and death from disease suggesting the importance of comprehensive staging in this cohort. PIK3CA appears to be a prognostic stratification feature within HR-NSMP and represents a potential therapeutic pathway. More work is needed to understand the association of HER2 expression and ER status and whether HER2 -targeted therapies represent actionable opportunities for these patients. Citation Format: Andrea Neilson, Amy Jamieson, Derek Chiu, Samuel Leung, Amy Lum, Jennifer Pors, Stefan Kommoss, Aline Talhouk, David G. Huntsman, Naveena Singh, C. Blake Gilks, Jessica N. McAlpine. High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B031.

Survival trends and prognostic factors of patients with newly diagnosed multiple myeloma accompanied with extramedullary disease

Background: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM). Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher’s exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model. Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p < 0.001). The EM-E group had the worst progression-free survival (PFS) and overall survival (OS). In addition, patients with multiple sites of EMD invasion or high Ki67 expression had poor OS. Lenalidomide-based treatment showed the worst outcome, and autologous stem cell transplantation (ASCT) remarkably improved the survival of patients with EMD. A prognostic model (MM prognostic index, MM-PI) comprising lactate dehydrogenase (LDH), circulating plasma cells (CPC), del(17p), and type of extramedullary involvement was developed, and a 4-factor nomogram. Conclusions: We established a risk model incorporating extramedullary disease that provides accurate and individualized survival estimates for patients with NDMM.

Abstract B104: The invisible divide: The impact of race and location on multiple myeloma outcomes in Arkansas

Abstract Cancer survival rates in the United States have seen remarkable improvements attributed to early detection, enhanced screening practices, and innovative treatments. However, these advancements have not translated equally to all communities, particularly among minorities and rural populations. This disparity is amplified by the prevalence of certain cancers, such as multiple myeloma (MM), which disproportionately affects older adults and exhibits significant ethnic disparities. Black people are 2-5 times more likely to develop the disease compared to those of European descent. MM is a malignancy of plasma cells and in 2023, it is expected that in the US there will be 35,730 new MM diagnoses and 12,590 associated deaths. This study focuses on MM patients in Arkansas, where racial segregation and rural population density contribute to healthcare access challenges and poorer outcomes. We retroactively analyzed a dataset composed of 4,639 patients treated at the University of Arkansas for Medical Sciences that have all received a transplant as part of their treatment. In this study, we performed a descriptive analysis of patients’ outcomes with MM treated in Arkansas. We look at the non-metro versus metro areas while also looking at racial differences in survival outcomes between Black and White patients. To pinpoint specific areas of Arkansas with high disparities, we divided the state into 6 regions. Taken in aggregate, there was no significant difference in progression-free survival (PFS) or overall survival (OS). Just looking at the best and worst performing regions, we compared the Central Arkansas region to the Lower Delta. A significant difference was observed in PFS and OS, with p-values of 0.00034 and 0.025, respectively. Patients from the Central region had a significantly higher survival probability. We observed a significant difference in PFS and OS by race (p-value 0.012 and 0.062). We see that Black patients from the Lower Delta had the worst PFS, and PFS was similar between Black and White patients from the Central region. Interestingly, White patients from the Lower Delta had the worst overall survival probability. Black patients from the Central region had the best OS. This research highlights the disparities between non-metro and metro MM patients, as well as the disparities between Black and White populations in Arkansas compared to the rest of the country. Rural region had the largest disparity in PFS and OS compared to the metro Central region of Arkansas. Black patients from the Lower Delta region have worse PFS than African Black patients from the Central region, and White patients from the Lower Delta region have worse OS than White patients from the Central region. These findings emphasize the importance of targeted education efforts aimed at physicians and patients in rural communities, which could potentially lead to significant improvements in MM outcomes and bridge the existing disparities. Citation Format: Michael A. Bauer, Mario Shootman, Chenghui Li, Frits Van Rhee, Samer Al Hadidi, Carolina D. Schinke, John D. Shaughnessy, Joseph L. Su, Fenghuang Zhan, Cody Ashby. The invisible divide: The impact of race and location on multiple myeloma outcomes in Arkansas [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B104.

Oligomannose-Type Glycans in the Antigen Binding Site Identify Origin and Prognosis of Diffuse Large B Cell Lymphoma

The acquisition of N-glycosylation sites (AGS) in the complementarity-determining region (CDR) of the tumor immunoglobulin (Ig) is an early clonal requirement of classic follicular lymphoma (FL). In FL, the AGS are occupied by oligomannose-type glycans, which mediate lymphoma Ig interaction with the microenvironmental lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). This interaction induces a persistent low-level signal, favouring adhesion and ultimately survival and growth of the lymphoma cells in their protected environment . Oligomannose-type glycans can also occupy the CDR-located AGS of a subset of germinal-centre B cell-like (GCB) diffuse large B-cell lymphomas (DLBCL) but the consequences of AGS in DLBCL are less known. We determined the frequency, distribution, and composition of the glycan structures occupying the AGS in DLBCL using a discovery-validation approach with two large independent international public cohorts (BCC, dataset ID: EGAD00001003783; NCI accession phs001444.v1.p1), following our RNAseq Ig assembly pipeline (Ig-Seq-R) and high-resolution mass-spectrometry. Glycan types were compared to our FL cohort (12 samples) and correlated with DLBCL cell of origin (COO), genetic, clinical characteristics and outcome. The full IGHV-IGHD-IGHJ-IGHC transcript sequences were obtained from 251 DLBCL of the BCC, and 339 of the NCI cohort. Sample distribution by COO, clinical or molecular features, LymphGen subtype, progression-free survival (PFS) and overall survival (OS) were not different from the extended public cohorts. AGS were observed in 48-55% GCB-DLBCL, with 84-85% of them located in the CDR. Overall, frequency of CDR-located AGS contrasted dramatically between GCB-DLBCL (41-46%) and activated B-cell like (ABC)-DLBCL (7-10%). Also, within GCB-DLBCL, CDR-located AGS associated mostly with the EZB subtype (68-73%). However, only 66-61% EZB were AGS+ve, all of which were CDR+ve, while the remaining 34-39% had no AGS (AGS-ve EZB). The glycan structures of the synthetic F(ab)s from 35 AGS+ve DLBCL and 12 FL were analyzed by site-specific mass spectrometry. The DLBCL comprised 12 AGS+ve EZB and 23 AGS+ve non-EZB (14 CDR+ve, 9 located in the framework region). Glycan analysis revealed that all AGS+ve EZB and FL were invariably occupied by oligomannose-type glycans (Ig-Mann+ve DLBCL). In contrast, the other AGS+ve DLBCL were not occupied by oligomannose type glycans. They were either occupied by complex glycans (the remaining non-EZB GCB-DLBCL) or not occupied (preferentially the ABC-DLBCL), irrespective of AGS location. These data indicated that CDR+ve EZB Ig were universally and exclusively Ig-Mann+ve DLBCL, share the COO of FL, and have likely been influenced by an environmental driver distinct from the other GCB-DLBCL and ABC-DLBCL. We compared the clinical behavior of Ig-Mann+ve DLBCL versus other DLBCL subtypes including AGS-ve EZB and the other non-EZB GCB-DLBCL and ABC-DLBCL. In both the BCC and NCI cohorts, Ig-Mann+ve DLBCL status identified the subset with the worst PFS and OS of all GCB-DLBCL, not different from ABC-DLBCL (Figure 1A). This contrasted with the other GCB-DLBCL (AGS-ve/EZB and AGS+ve/non-EZB), which all shared an extremely good PFS and OS (Figure 1A). Univariate and multivariate analyses revealed that Ig-Mann+ve status was an independent prognostic factor for PFS and OS (Figure 1B). Gene expression profile analysis revealed that Ig-Mann+ve status associated with an enrichment of MYC, PI3K-Akt-mTORC1, pro-survival, and cell cycle pathways, while proinflammatory and apoptotic pathways were decreased in the Ig-Mann+ve DLBCL compared to AGS-ve/EZB and AGS+ve/non-EZB, independently of MYC translocations and double-hit signature. These data indicate identical COO of a EZB subset with FL cells, and point to a highly selective chronic environmental pressure on Ig-Mann+ve DLBCL negatively affecting patients survival. The combination of Ig gene analysis with the lymphGen classification can predict Ig glycan structure and provide a new fundamental approach to identifying the most aggressive GCB-DLBCL subtype, and the precise environmental tumour interaction (DC-SIGN:Ig-Mann) to intercept therapeutically early in the natural history of Ig-Mann+ve DLBCL.

Survival Trends and Prognostic Factors of Patients with Newly Diagnosed Multiple Myeloma Accompanied with Extramedullary Disease

Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM). A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B), and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model. Compared to patients without EMDs, patients with EM-E were younger ( P=0.028), and those with EM-B had less renal damage ( P&amp;lt;0.001). The EM-E group had the worst progression-free survival (PFS) and overall survival (OS). In addition, patients with multiple sites of EMD invasion or high Ki67 expression had poor OS. Lenalidomide-based treatment showed the worst outcome, and autologous stem cell transplantation (ASCT) remarkably improved the survival of patients with EMD. A prognostic model (MM prognostic index, MM-PI) comprising lactate dehydrogenase (LDH), circulating plasma cells (CPC), del(17p), and type of extramedullary involvement was developed, and a 4-factor nomogram. In conclusion, we established a risk model incorporating extramedullary disease that provides accurate and individualized survival estimates for patients with NDMM.

Efficacy and Safety of Ibrutinib in Relapsed or Refractory Marginal Zone Lymphomas: The “Real World” Italian Experience

Introduction Ibrutinib was the first FDA-approved drug for patients (pts) with relapsed or refractory (R/R) marginal zone lymphomas (MZL), based on a phase 2 trial showing an overall response rate (ORR) of 58%, a median progression-free survival (PFS) of 15.7 months (mo) and an acceptable safety profile (Noy 2021). However, accelerated approval was voluntarily withdrawn in the US in April 2023, while it was never released by EMA. Currently, very few real world data about ibrutinib or other BTK inhibitors are available, and none from European countries. Methods Since November 2020 ibrutinib was available in Italy for the treatment of R/R MZL based on 648/96 Italian national law. We designed a retrospective multicentre study with the aim to evaluate efficacy and safety of ibrutinib administered until progression or unacceptable toxicity in pts with R/R MZL of either splenic, nodal, extranodal or disseminated subtype (SMZL, NMZL, EMZL, dissMZL). The study was approved by the IRB of the 19 participating centers. All pts signed informed consent. The primary endpoints were ORR and PFS. Results We enrolled 79 pts (45 males), including 48 SMZL, 14 NMZL, 12 EMZL and 5 dissMZL. Median age was 74 years (42-88). Median number of prior therapies was 1 (1-5). Rituximab monotherapy was the only prior line in 7 pts (9%), while 72 (91%) received at least 1 prior immuno-chemotherapy regimen (BR in 74%). Sixteen pts (20%) were primary refractory, 37 (47%) were classified as POD24 and 21 (27%) were refractory to the last therapy. TP53 deletion or mutation was detected in 10/21 available samples from SMZL cases (48%). Median duration of drug exposure was 10.6 mo (95% CI 1.1-27.6). ORR was 72% (Tab 1), including 10 pts (13%) achieving a complete response (CR) and 47 (59%) a partial response (PR) (Tab 1). Median time to initial response was 3.4 mo (95% CI 0.9-10.5) and median time to best response was 6.1 mo (95% CI 1.6-16.8). NMZL or dissMZL sutype (OR 3.3, p=0.05) and pre-ibrutinib ECOG &amp;gt;1 (OR 8.2, p=0.008) independently predicted probability of non-response. At a median follow-up of 13.4 mo (95% CI 1.9-29.6), 29 pts progressed, including 12 responders. Median PFS was 20.5 mo (95% CI 12.3-NR, Fig 1), while median duration of response (DOR) among 57 responders was not reached (estimated 18-mo DOR 64.2%, 95% CI 43.3-79.2). None of the pts who achieved CR progressed, compared with 12/47 of those who achieved PR (18-mo DOR 100% vs 54.5%, p=0.051). At Cox regression multivariate analysis, pre-ibrutinib ECOG &amp;gt;1 (HR 2.09, 95% CI 1.19-3.67, p=0.01), elevated LDH (HR 2.56, 95% CI 1.13-5.79, p=0.024) and NMZL or dissMZL subtypes (HR 3.46, 95% CI 1.57-7.63, p=0.002) were associated to a worst PFS. Interestingly, pre-ibrutinib MZL-IPI,including the latter two factors plus platelet count &amp;lt;100 x 10 9/l, Hb &amp;lt;12 g/dl and absolute lymphocytes count &amp;lt;1 x 10 9/l ( Luminari ICML23), significantly predicted distinct PFS according to low (0, n=6, 8%, 18-mo PFS 100%), intermediate (1-2, n=50, 63%, 18-mo PFS 59%) and high risk classes (≥3, n=23, 29% 18-mo PFS 26%) (p=0.011). POD24, primary refractoriness, refractoriness to last therapy number and types of prior lines had no influence on PFS. TP53 mutation or deletion resulted significantly associated to inferior PFS in SMZL cases (p=0.015). Overall, 32 pts (40.5%) discontinued ibrutinib, 11 for adverse events (AEs) and 21 for progressive disease (PD). Hematologic AEs were reported in 13 pts, including grade (Gr) 3-4 in 8, 10% (anemia in 4, thrombocytopenia in 3 and neutropenia in 1), while extra-hematologic AEs in 39 (49%) (Gr 3-5 in 15, 19%). The most common AEs were atrial fibrillation (n=8, 10%), bleeding (n=7, 9%), rash (n=6, 8%), diarrhea in 5 (6%), and infections (n=12, 15%), which included 3 Gr 3-4 (COVID-19, pneumonia, sepsis) and 4 Gr 5 events (septic shock in 2, aspergillosis and pneumonia). Histologic transformation was detected in 8 pts (10%). A post-progression therapy was initiated in 23 pts, resulting in ongoing CR/PR in 15. Overall, 11 pts died (6 due to PD, 4 infections, 1 suicide), with a 18-mo overall survival (OS) of 81.2% (95% CI 63.9-89.4). Not achieving ORR significantly predicted worst OS (HR 6.43, 95% CI 1.87-22.09, p=0.003). Conclusions Our data confirmed that ibrutinib is associated with high ORR and durable disease control in R/R MZL in real life. Toxicity was similar to what previously reported in the registration phase 2 study in R/R MZL and in other histologies. Careful attention to infectious toxicity is advised.

Allelic Context of EGFR C797X–Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes

IntroductionEGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts. MethodsWe identified patients with EGFR C797X–mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status. ResultsA total of 365 EGFR C797X–mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7–8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype. ConclusionsAllelic context could define four EGFR C797X–mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.

Evolving treatments and outcomes in HER2-Positive metastatic breast cancer: Data from the GIM14/BIOMETA study

BackgroundTreatment for HER2-positive (+) metastatic breast cancer has improved in the last decade. We analyzed treatment changes over time and their impact on patients outcomes in a real-world dataset. MethodsData from 637 HER2+ patients with metastatic breast cancer enrolled in the multicenter Italian GIM14/BIOMETA study were retrieved. Progression-free survival (PFS) over time was evaluated according to the type of anti-HER2 therapy, disease onset (de novo vs. relapsing), metastatic site, and year of treatment (2000–2013 vs. 2014–2020). ResultsMedian follow-up was 64.4 months. Overall, for first-line therapies, mPFS was 16.5 vs 19.5 months for patients treated in 2000–2013 vs 2014–2020 (HR: 0.78, 95% CI:0.65–0.94, P = 0.008). mPFS improved over time in all patients except for those with brain metastasis. Interestingly mPFS was 17.4 vs13.4 months (HR, 1.49; 95% CI, 1.13–1.98, P = 0.005) in 2000–2013 and 24.4 vs 20.9 months (HR 1.04; 95% CI 0.78–1.40 p = 0.77) in 2014–2020 in pts without vs with liver metastases. For second line therapies, the overall median PFS was 9.6 months (95% CI, 8.31–10.97) and did not change over time. ConclusionMedian first-line PFS improved since 2014, mainly due to the introduction of pertuzumab. The outcome of patients with liver metastases appears to have improved in recent years. Patients with brain metastases had the worst PFS, which also did not improve over time.

Prognosis of patients with T1 low-grade urothelial bladder cancer treated with bacillus Calmette-Guérin immunotherapy.

The existence and prognosis of T1LG (T1 low-grade) bladder cancer is controversial. Also, because of data paucity, it remains unclear what is the clinical history of bacillus Calmette-Guérin (BCG) treated T1LG tumors and if it differs from other NMIBC (non-muscle-invasive bladder cancer) representatives. The aim of this study was to analyse recurrence-free survival (RFS) and progression-free survival (PFS) in patients with T1LG bladder cancers treated with BCG immunotherapy. A multi-institutional and retrospective study of 2510 patients with Ta/T1 NMIBC with or without carcinoma in situ (CIS) treated with BCG (205 T1LG patients) was performed. Kaplan-Meier estimates and log-rank test for RFS and PFS to compare the survival between TaLG, TaHG, T1LG, and T1HG NMIBC were used. Also, T1LG tumors were categorized into EAU2021 risk groups and PFS analysis was performed, and Cox multivariate model for both RFS and PFS were constructed. The median follow-up was 52 months. For the T1LG cohort, the estimated RFS and PFS rates at 5-year were 59.3% and 89.2%, respectively. While there were no differences in RFS between NMIBC subpopulations, a slightly better PFS was found in T1LG NMIBC compared to T1HG (5-year PFS; T1LG vs. T1HG: 82% vs. 89%; P<0.001). A heterogeneous classification of patients with T1LG NMIBC was observed when EAU 2021 prognostic model was applied, finding a statistically significant worse PFS in patients classified as high-risk T1LG (5-year PFS; 81.8%) compared to those in intermediate (5-year PFS; 93,4%), and low-risk T1LG tumors (5-year PFS; 98,1%). The RFS of T1LG was comparable to other NMIBC subpopulations. The PFS of T1LG tumors was significantly better than of T1HG NMIBC. The EAU2021 scoring model heterogeneously categorized the risk of progression in T1LG tumors and the high-risk T1LG had the worst PFS.

T cell engager (TCE) score in patients treated with bispecific CD3 TCE in phase I clinical trials.

2573 Background: Immune prognostic scores, such as the Gustave Roussy Immune (GRIM) score have been investigated in patients (pts) treated with immune check-point blockers. We aimed to determine whether we could improve the selection of pts that could benefit from new immunotherapies such as bispecific CD3 T cell engagers (TCE) antibodies in pts treated in phase I clinical trials (CT), by building a new prognostic score. Methods: All patients treated with bispecific CD3 TCE in phase I CT from July 2018 to February 2023 at the Drug Development Department at Gustave Roussy were enrolled in the study. Univariate and multivariate analyses (UVA and MVA) were conducted on demographic, clinical and biological data to assess their prognostic value on progression free survival (PFS). MVA results were used to build a new prognostic score (TCE score). This score was then validated on overall survival (0S). The predictive ability (on PFS and OS) of the TCE score was assessed using Harrell’s C index. It was compared with the GRIM and Royal Marsden Hospital (RMH) scores predictive ability on PFS and OS. Results: A total of 67 patients (47 men, 20 women) with metastatic solid cancer or advanced hematological cancer were included. Median age was 62 years old. The most represented tumor types were prostate cancer (33%), lymphoma (25%) and small cell lung carcinoma (24%). UVA on PFS showed that elevated C-reactive protein (CRP) (HR: 2,36; 95%CI: 1,35-4,16; p = 2.10-3) and lactate dehydrogenase (LDH) (HR: 3,00; 95%CI: 1,63-5,53; p = 2.10-4) were associated with a worst PFS. In MVA, LDH (HR: 2,49; 95% CI: 1,30-4,74, p = 1.10-4) and CRP levels (HR: 1,92; 95% CI: 1,1-3,46; p = 1.10-4) were independent negative prognostic factors for PFS. The TCE score was based on MVA results (CRP&gt;10g/l: +1; LDH &gt; 250U/l: +1). It showed that pts with a high score (1-2) had a shorter PFS (median PFS: 2,8 months) and OS (median OS: 9,9 months) than low score (0) pts (median PFS: 5,8 months; median OS: not reached). TCE score’s Harrell’s C index for PFS was 0,63 and 0,64 for OS. For GRIM and RMH scores, Harrell’s C index for PFS were respectively 0,60 and 0,55. For OS it was respectively 0,58 and 0,53. Conclusions: To select patients for Bispecific CD3 TCE phase I CT, we built a new prognostic score, based on LDH and CRP levels, that can be used as prognostic of PFS and OS. TCE score is more reliable than GRIM and RMH scores to prognose PFS and OS.

Dynamic changes in circulating EBV-DNA load during treatment have prognostic values in EBV+ DLBCL-NOS: a Chinese cohort study.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL-NOS), is an EBV-positive clonal B-cell lymphoid proliferation and circulating EBV-DNA is a great indicator for prognosis among EBV associated disease. In this retrospective study, we report 66 EBV+ DLBCL cases among 2137 DLBCL-NOS cases diagnosed from 2013 to 2021 (prevalence of 6.0%). After a median follow-up of 27months, progression-free survival (PFS) and overall survival (OS) at 2years were 39.5% ± 6.2% and 53.6% ± 6.4%, respectively. Multivariate analysis showed that only the biomarker of the positivity of post treatment EBV-DNA had a borderline correlation with shorter PFS and OS (PFS: P = 0.053; OS: P = 0.065). Patients were divided into three subgroups according to dynamic changes of EBV-DNA status: EBV-DNA persistently negative group, EBV-DNA persistently positive group, and EBV-DNA transformed from positive to negative group; among the three groups, patients of the persistently positive group had worst PFS and OS (P = 0.0527 and P = 0.0139, respectively). Decline in EBV copies correlated significantly with treatment response as well. In conclusion, circulating EBV-DNA level played a vital role in prognostic and monitoring marker for EBV+ DLBCL-NOS.

P52 RISK STRATIFICATION COMBINING SKY92 GENE EXPRESSION PROFILING AND TRADITIONAL FISH IN MULTIPLE MYELOMA: THE FIRST PROSPECTIVE EVIDENCE IN THE R2-ISS ERA

High-risk (HR) multiple myeloma (MM) patients still have a very poor prognosis. However, the definition of HR MM remains controversial. Currently, FISH is the most commonly used method for risk stratification in MM. According to the Second Revised International Staging System (R2-ISS), HR cytogenetics is defined as presence of at least one of the following: del(17p), t(4;14), and 1q CNA. In recent years, gene expression profiling (GEP) approaches, e.g. SKY92, have been developed for detection of HR patients. In the R2-ISS era, however, data on MM risk stratification applying SKY92 in combination with traditional FISH is still lacking. Therefore, we performed the first prospective study evaluating the prognostic value of the combined SKY92 and FISH HR detection in newly diagnosed (ND) and relapsed/refractory (RR) MM. We prospectively collected bone marrow (BM) samples and clinical data of 147 MM patients. Cytogenetics were analyzed on purified CD138 positive MM cells by FISH, and HR cytogenetics was defined according to the R2-ISS classification. SKY92 risk status was determined with MMprofiler gene expression assay. Whole genome sequencing (WGS) was performed to compare the both risk stratification systems SKY92 and FISH. We included 147 patients in our study (NDMM: n=51, RRMM: n=96). SKY92 classification was available for 121 (82.3%) patients. HR SKY92 was significantly enriched in RRMM (40/76) compared with NDMM (6/45) (P<0.0001). RRMM patients with HR SKY92 showed significantly shorter progression free survival (PFS) (P<0.0001) and overall survival (OS) (P=0.0004) than standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (P=0.001) in comparison with SR. Of note, samples of 26 (17.7%) patients, who showed significantly lower bone marrow infiltration than the remaining patients (median: 25% vs 55%, P=0.038), did not meet the SKY92 quality control criteria. We then combined the SKY92 classification with cytogenetic analyses by FISH, which were available in 99 patients (NDMM: n=33; RRMM: n=66). We noticed a discrepancy between both risk stratification systems, with 44 (44.4%) and 58 (58.6%) patients being classified as HR by SKY92 and FISH, respectively. In total, 28 (42.4%) RRMM patients and 6 (18.2%) NDMM patients displayed HR in both SKY92 and FISH (double-HR). Regarding survival outcome in RRMM, double-HR patients showed the worst PFS (P<0.0001) and OS (P=0.0007). In NDMM, double-HR presented a negative prognostic factor for PFS (P=0.01). To compare the FISH and SKY92 classifications, we performed WGS in 16 patients who exhibited either only HR SKY92 (n=7) or only HR FISH (n=9). Interestingly, 1 patient with bi-allelic TP53 inactivation (deletion + mutation) and 6 patients harbouring 1q CNA were determined as SR by SKY92 but as HR by FISH. The median PFS was not reached after a median follow up of 371 days in these 9 patients. Moreover, 4 out of 7 patients with only HR SKY92 but SR FISH displayed 1q CNA, which was detected only by WGS, and del1p32 was found in 1 patients. Interestingly, we found CRBN mutation in 3 out of 7 patients with only HR SKY92 but SR FISH. The remaining 2 patients did not show any known HR genomic alterations, suggesting that HR MM may be associated with other factors, e.g. epigenetic modifications. Here, we provide the first prospective evidence in the R2-ISS era that advanced risk stratification combining SKY92 and FISH may help to identify the highest-risk MM.

Abstract 5470: Identification of gene amplification based signature as predictors for chemotherapy in squamous cell carcinoma of the lung

Abstract Background: Lung squamous cell carcinoma (LUSC) is the second most popular histologic subtype accounting for 25%~30% of lung cancer. Due to the lack of targeted therapies for LUSC, the prognosis is poor and chemotherapy still plays a full role in the treatment of LUSC patients currently. However, a significant proportion of patients showed a bad response to chemotherapy. The development of predictive biomarkers is urgent. We aimed to identify new chemotherapy biomarkers based on genomic alterations. Methods: We retrospectively analyzed DNA sequencing data of 317 LUSC patients (pts) at West China hospital. We collected the clinical features and progression-free survival (PFS) of 35 pts with chemotherapy only. Pts were assigned to different subgroups based on genomic alterations using non-negative matrix factorization (NMF) clustering. Based on the characteristics of the cluster, we then explored clear gene signatures to predict the prognosis of chemotherapy. The clinical information and sequencing data of TCGA LUSC with chemotherapy were used to validate the prognostic value of the signature. Results: The 317 LUSC pts were grouped into 4 clusters characterized by different genomic alterations. Cluster 1 (C1) had 129 pts and was characterized by TP53 alterations. There were 116 pts in cluster 2 (C2) characterized by PIK3CA amplification (amp). Cluster 3 (C3) had 33 pts and was characterized by gene amp of CCND1, FGF3, FGF4, and FGF19. Cluster 4 (C4) was characterized by gene amp of FGFR1, KDR, KIT, and PDGFRA. The 35 pts treated with chemotherapy only were also classified into 4 clusters. C1 was associated with the shortest PFS (hazard ratio (HR), 2.87; 95% confidence interval (CI), 1.15-7.13; p = 0.018) independently of the clinical stage, but C2, C3, and C4 showed no significant difference. In addition, we also found that pts with TP53 loss of function (LOF) alteration had significantly shorter PFS than those without TP53 LOF (wildtype or not LOF, p = 0.029). So we further modified the clustering by TP53 alteration from C1 and gene amp from C2, C3, and C4. Therefore, 35 pts were then grouped into 3 subtypes based on TP53 LOF and gene amp characteristics, and the PFS was significantly different. Pts (n = 8, 23%) with at least one amp of 9 genes (PIK3CA, CCND1, FGF3, FGF4, FGF19, FGFR1, KDR, KIT, and PDGFRA) but no TP53 LOF had the longest PFS (HR, 0.12; 95% CI, 0.02-0.66; p = 0.011). Pts (n = 6) with TP53 LOF but no 9-gene amp had poor survival compared with pts in other subtypes. This gene signature was validated in TCGA pts. The signature of 9-gene amp without TP53 LOF also indicated the best PFS and TP53 LOF without 9-gene amp indicated the worst PFS (p = 0.081). Conclusion: We develop a biomarker signature that consists of 9-gene amp and TP53 LOF to indicate the prognosis of chemotherapy. Our results suggest that 9-gene amp without TP53 LOF in LUSC is a favorable prognostic marker for patients taking chemotherapy. Citation Format: Yuan Tang, Yuli Li, Ting Hou, Lili Jiang, Hongjie Liu, Chunxiao Pan, Weiya Wang, Li Qiu, Yajing Zhang, Guiping Zhang, Ke Zheng. Identification of gene amplification based signature as predictors for chemotherapy in squamous cell carcinoma of the lung. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5470.

PD10-11 DISTINCT CLINICAL GENOMIC VARIATIONS AMONG MEN WITH LOCALIZED VS METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD10-11 DISTINCT CLINICAL GENOMIC VARIATIONS AMONG MEN WITH LOCALIZED VS METASTATIC PROSTATE CANCER Ahmed El-shafie, Mohammed Al-Toubat, Allison H. Feibus, SeyedBehzad Jazayeri, Soroush Bazargani, Devon Thomas, Mark Bandyk, and K.C. Balaji Ahmed El-shafieAhmed El-shafie More articles by this author , Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , SeyedBehzad JazayeriSeyedBehzad Jazayeri More articles by this author , Soroush BazarganiSoroush Bazargani More articles by this author , Devon ThomasDevon Thomas More articles by this author , Mark BandykMark Bandyk More articles by this author , and K.C. BalajiK.C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003250.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Our objective was to identify unique genetic mutations associated with metastatic prostate cancer (PCa) by comparing next generation sequencing (NGS) data between men with localized and metastatic disease METHODS: We queried the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry for men diagnosed with PCa. Patients were categorized into localized (m0) and metastatic (m1) groups. The difference in the frequency of genetic mutations between the two groups and the prognostic significance of the differentially expressed genes were analysed using SPSS V24. We included frequency rates of >5% and p values <0.05 were considered statistically significant to maintain over 95% true positive detection rate. RESULTS: A total of 1,027 patients, with localized (n=459) and metastatic PCa (n=568) were included in the study. Patients were mostly non-Hispanic White men (89%) with a median age of 61 years (IQR 56-66 years). 421 (41%) of our cohort had Gleason grade group (GG) 2 disease, 277 (27%) had GG3 disease, and 267 (26%) had GG4 or GG5 disease. We identified alterations in 89 genes in our analyses. Patients with M1PCa had significantly higher genomic aberrations in TMPRSS2 (31.51% vs 11.14%, p<0.001); ERG fusion (23.59% vs 13.13%, p<0.001); PTEN loss (25.7% vs 16.16%, p<0.001); TP53 mutation (38.73% vs 12.23%, p<0.001); FOXA1 (17.43% vs 6.33%, p<0.001); KMT2C (9.51% vs 6.11%, p=0.02) (Figure 1). We then isolated the signalling pathways most likely to be affected by these mutations, and found that the androgen receptor was most often impacted (Figure 2). Patients with alterations in all 6 of the genes listed above had the worst progression-free survival (p = <0.01, log rank test) (Figure 1). CONCLUSIONS: In M1PCa, patients had significantly higher frequency of TMPRSS2, ERG, PTEN loss, TP53, FOXA1, and KMT2C somatic gene mutations compared to samples from patients with m0PCa. Additionally, patients who had mutations in all 6 of these genes harboured more aggressive cancer and poorer outcomes. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e330 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed El-shafie More articles by this author Mohammed Al-Toubat More articles by this author Allison H. Feibus More articles by this author SeyedBehzad Jazayeri More articles by this author Soroush Bazargani More articles by this author Devon Thomas More articles by this author Mark Bandyk More articles by this author K.C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...

Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis.

Gut microbiota can significantly affect the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. Recently, antibiotics were shown to decrease survival rate of patients treated by ICIs. Proton pump inhibitors (PPIs) can indeed modulate microbiota's diversity, therefore altering ICIs response. A meta-analysis was performed based on published data to verify this hypothesis. In this study, over 41 publications, exploring the impact of concomitant PPI treatment on outcomes of ICI-treated patients, were analyzed. Evaluated endpoints were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) with a 95% confidence interval (CI) were reported in ICIs in PPI users versus non-PPI users. Subgroup analyses were performed to minimize the impact of study heterogeneity and to investigate the influence of PPI on the different groups of interest. There was no evidence of publication bias for OS and PFS analysis in subgroup analysis. Forty-one studies were included in the meta-analysis, including a total of 20,042 patients. OS of patients receiving ICIs was negatively correlated in patients concomitantly treated with PPI (HR=1.37; 95%CI, 1.23-1.52). PFS of cancer patients receiving ICIs was also negatively correlated with PPI treatment (HR=1.28; 95%CI, 1.15-1.42). PPI and ICI use was associated with worst OS and PFS not only for non-small-cell lung cancer (NSCLC) or urothelial cancer patients but also for patients treated with anti PD-1 (OS) and anti PD-L1 (OS and PFS) immunotherapies when administered in non-first line and when PPI was received as baseline treatment or in 60 days before ICI initiation. PPI and ICI use also showed the worst OS and PFS for patients from Europe and Asia. This meta-analysis suggests that PPI treatment leads to significantly worse outcomes in advanced cancer patients treated by ICIs in terms of PFS and OS.

Using publicly available datasets to identify population-based transcriptomic landscape contributing to the aggressiveness of breast cancer in young women.

Introduction: Although the risk of breast cancer increases with advancing age, some regions have larger number of young breast cancer patients (≤45years-old), such as the Middle East, Eastern Asia, and North Africa, with more aggressive and poorly differentiated tumors. We aimed to conduct an in-silico analysis in an attempt to understand the aggressive nature of early-onset breast cancer, and to identify potential drivers of early-onset breast cancer using gene expression profiling datasets in a population-dependent manner. Methods: Functional genomics experiments data were acquired from cBioPortal database for cancer genomics, followed by the stratification of patients based on the age at representation of breast cancer and race. Differential gene expression analysis and gene amplification status analysis were carried out, followed by hub gene, transcription factor, and signalling pathway identification. Results: PAM50 subtype analysis revealed that young patients (≤45years-old) had four-fold more basal tumors and worst progression-free survival (median of 101months), compared with the 45-65years group (median of 168months). Fourteen genes were amplified in more than 14% of patients with an early-onset breast cancer. Interestingly, FREM2, LINC00332, and LINC00366 were exclusively amplified in younger patients. Gene expression data from three different populations (Asian, White, and African) revealed a unique transcriptomic profile of young patients, which was also reflected on the PAM50 subtype analysis. Our data indicates a higher tendency of young African patients to develop basal tumors, while young Asian patients are more prone to developing Luminal A tumors. Most genes that were found to be upregulated in younger patients are involved in important signaling pathways that promote cancer progression and metastasis, such as MAPK pathway, Reelin pathway and the PI3K/Akt pathway. Conclusion: This study provides strong evidence that the molecular profile of tumors derived from young breast cancer patients of different populations is unique and may explain the aggressiveness of these tumors, stressing the need to conduct population- based multi-omic analyses to identify the potential drivers for tumorigenesis and molecular profiles of young breast cancer patients.