BC Subtypes Research Articles

Epidemiological dynamics and molecular characterization of HIV drug resistance in eastern China from 2020 to 2023

ObjectiveHIV drug resistance (HIVDR) has become a threat to the elimination of the AIDS epidemic due to the global scale-up of antiretroviral therapy (ART) for HIV-infected individuals. This study aims to investigate the epidemiological dynamics and molecular characterization of HIV pretreatment drug resistance (PDR) and acquired drug resistance (ADR) in Hangzhou, a developed region in China.MethodsAn epidemiological survey combined with a molecular transmission network and Bayesian analysis was conducted. A total of 3,596 individuals with newly confirmed HIV infections (from 2020 to 2023) and 164 individuals with ART failure (from 2021 to 2023) were included. The molecular transmission network was used to identify key drug-resistant transmission clusters, while the Bayesian analysis was utilized to trace the origins and spread of these clusters.ResultsThe overall prevalence of PDR was found to be 8.4% (303/3596). Among these cases, PDR to non-nucleoside reverse transcriptase inhibitors (NNRTIs) accounted for 4.7% (170/3596), significantly higher than the resistance observed for protease inhibitors (PIs; 2.8%, p < 0.001) and nucleoside reverse transcriptase inhibitors (NRTIs; 1.4%, p < 0.001). Multivariate logistic regression analysis revealed a significantly higher PDR value among individuals infected with the CRF07_BC subtype compared to those with the CRF08_BC subtype (aOR = 0.56, 95% CI = 0.359–0.859, p = 0.008). The molecular transmission network analysis identified the transmission of the drug resistance mutation (DRM) Q58E within the clusters of the CRF07_BC subtype. The Bayesian analysis suggested that these clusters were introduced into Hangzhou from Shenzhen between 2005 and 2012. Furthermore, the study highlighted 50.6% (83/164) prevalence of ADR among individuals experiencing ART failure. The combined molecular network analysis of virological failure and newly confirmed HIV infections indicated the transmission of the K103N mutation between these groups.ConclusionIn conclusion, targeted interventions may be necessary for specific subtypes and transmission clusters to control the spread of drug-resistant HIV. Continuous monitoring of resistance patterns is critical to inform treatment strategies and optimize ART regimens.

Transmitted drug resistance and molecular transmission network among treatment-naive HIV-1 patients in Wenzhou, China, 2020–2023

BackgroundTransmitted drug resistance (TDR) increases the risk of antiretroviral therapy (ART) failure in HIV-1 patients. This study investigated the molecular epidemiology of TDR and its transmission networks among newly diagnosed HIV-1 patients in Wenzhou, China.MethodsWe enrolled 1878 ART-naive HIV-1 patients from January 2020 to October 2023. TDR was evaluated using the Stanford University HIV Drug Resistance Database. We performed phylogenetic analysis, genotyping, transmission clustering, and population-based TDR-related factor analysis.ResultsAmong 1782 patients with successful genotyping, TDR prevalence was 5.7%. Multivariable analysis identified CRF08_BC subtype (adjusted odds ratio [aOR] 18.59, 95% CI 3.79-336.18, p = 0.004), CD4 > 500 cells/mm³ (aOR 2.19, 95% CI 1.16–4.03, p = 0.013), and year 2023 (aOR 1.83, 95% CI 1.11–4.89, p = 0.039) as factors associated with higher TDR risk. The most prevalent NNRTI mutations were K103N, E138A, and V179E. Seven TDR transmission clusters were identified, notably one with V179D that expanded during 2020–2023.ConclusionsWhile TDR prevalence in Wenzhou remained lower than in other Chinese regions, an upward trend was observed. Most resistant individuals were in transmission clusters, predominantly middle-aged and elderly. NNRTI resistance was severe and concentrated in efavirenz, nevirapine, and rilpivirine. Enhanced HIV surveillance and wider free antiretroviral options are crucial to control drug-resistant HIV spread in Wenzhou.

Triple-negative breast cancer-derived exosomes change the immunological features of human monocyte-derived dendritic cells and influence T-cell responses.

Triple-negative breast cancer (TNBC) exhibits a lower survival rate in comparison to other BC subtypes. Utilizing dendritic cell (DC) vaccines as a form of immunotherapy is becoming a promising new approach to cancer treatment. However, inadequate immunogenicity of tumor antigens leads to unsatisfactory effectiveness of the DC vaccines. Exosomes are the basis for the latest improvements in tumor immunotherapy. This study examined whether TNBC-derived exosomes elicit immunogenicity on the maturation and function of monocyte-derived DCs and the impact of the exosome-treated monocyte-derived DCs (moDCs) on T cell differentiation. exosomes were isolated from MDA-MB-231 TNBC cancer cells and characterized. Monocytes were separated from peripheral blood mononuclear cells and differentiated into DCs. Then, monocyte-derived DCs were treated with TNBC-derived exosomes. Furthermore, the mRNA levels of the genes and cytokines involved in DC maturation and function were examined using qRT-PCR and ELISA assays. We also cocultured TNBC-derived exosome-treated moDCs with T cells and investigated the role of the treatment in T cell differentiation by evaluating the expression of some related genes by qRT-PCR. The concentration of the cytokines secreted from T cells cocultured with exosome-treated moDCs was quantified by the ELISA assays. Our findings showed that TNBC-derived exosomes induce immunogenicity by enhancing moDCs' maturation and function. In addition, exosome-treated moDCs promote cocultured T-cell expansion by inducing TH1 differentiation through increasing cytokine production. TNBC-derived exosomes could improve vaccine-elicited immunotherapy by inducing an immunogenic response and enhancing the effectiveness of the DC vaccines. However, this needs to be investigated further in future studies.

Abstract C147: Impact of genetic ancestry in triple-negative breast cancer subtypes

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive BC subtype characterized by significant molecular and clinical heterogeneity, influenced by genetic, phenotypic, and environmental factors, as well as interactions of the tumor with its surrounding milieu. A significant racial disparity has been observed between African American (AA) and European American (EA) women regarding the incidence and clinical progression of TNBC. TNBC frequently occurs in young parous women who self-identify as AA and in women who harbor a germline BRCA1 mutation. Notably, AA women are diagnosed with TNBC at a younger age and exhibit a higher risk of developing stage IV disease. Studies examining gene expression signatures that distinguish AA and EA TNBC have reported distinct tumor-associated immunologic profiles in AA patients. We have developed a novel cell type-driven subtyping system based on a racially diverse TNBC sample set that identified three TNBC subtypes, each with distinct biology and prognosis: CC1- immune signaling/T-cell response; CC2- pro- migratory/inflammatory; CC3- fatty acid and hormone and nuclear receptor signaling. In this study, we propose to examine ancestry-inferred differences within each TNBC subtype between patients with African and European ancestry. Methods: RNA-Sequencing data for the Louisiana Tumor Registry, a TNBC cohort of 250 diverse women [EA: 123 and AA: 127], was obtained from our collaborators at Louisiana State University Health Sciences Center. Genetic admixture was performed on 227/250 patients using the method described by Pakstis, A. J. et al. Differentially expressed genes (DEGs) were identified in pairwise comparisons at p-adj ≤ 0.05. Survival was assessed using log-rank tests. Results: We investigated DEGs within each subtype between patients with >60% African (Aa, n=102) or >60% European ancestry (Ea, n=99) (identified via admixture analysis). In all three subtypes, upregulated genes, and their associated enrichment in Aa were related to immune pathways, while DEGs in Ea patients were related to epithelial cell regulation. In CC1, Aa was associated with the upregulation of immunoglobulin genes involved in immunoglobulin production and antigen recognition, while Ea was associated with the upregulation of embryonic development genes. In CC2, Aa showed enriched complement activation and immunoglobulin genes, while Ea exhibited upregulation of basal cytokeratin and growth factor EGFR. In CC3, Aa was associated with the upregulation of inflammatory genes, whereas Ea showed upregulation of cellular senescence genes. Survival analysis demonstrated favorable outcomes for Aa in CC1 and less favorable outcomes for Aa in CC2. Conclusion: Our study highlights significant ancestry-inferred differences in gene expression within TNBC subtypes, with Aa patients showing immune pathways enrichment and Ea patients exhibiting differential epithelial cell regulation. These findings underscore the importance of considering genetic ancestry in TNBC prognosis and treatment strategies. Citation Format: Zahra Mesrizadeh, Kavitha Mukund, Fokrul Hossain, Jovanny Zabaleta, Denise Danos, Luis De Valle, Xiao-Cheng Wu, Chindo Hicks, Augusto Ochoa, Lucio Miele, Victoria L. Seewaldt, Shankar Subramaniam. Impact of genetic ancestry in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C147.

417P EV derived miR-21 as a promising biomarker for early diagnosis and tumor activity in discrete BC subtypes: The Exobreast project

417P EV derived miR-21 as a promising biomarker for early diagnosis and tumor activity in discrete BC subtypes: The Exobreast project

Current and Novel Treatment Options in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Metastatic breast cancer (mBC) remains an incurable disease, and most patients will experience disease progression during their treatment course. Although endocrine therapy remains the mainstay of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC, significant progress has been and continues to be made in the treatment of this BC subtype. The discovery of molecular markers, mutations in key cellular pathways, and genomic signatures have led to the development of novel and targeted agents, such as antibody-drug conjugates, oral selective estrogen receptor downregulators, and inhibitors of the PI3K/AKT/mTOR pathway. This has resulted in significant improvements in the survival and quality of life of patients. With the increasing number of treatment options for patients, appropriate drug sequencing remains a challenge. Treatment discussions should involve patient-physician shared decision making, with consideration of genomic data, previous lines of therapy, side effect profiles, and clinical trial enrollment.

Evaluating interaction between tumor educated platelets and cancer stem cells on breast cancer subtypes.

5 Background: Thrombocytosis has been reported to be responsible for poor prognosis of numerous malignancies. This swarm of platelets acts as foe for the body but as mate for the cancer cells by providing a protective shield around them, helping them to escape immunosurveillance process. A bidirectional interaction between platelets and tumor cells promote their conversion to an activated tumor educated platelet (TEP) state. The present report reveals the critical role played by TEPs to promote metastasis in BC subtypes by interacting with cancer stem cells (CSCs). Methods: Status of intra-tumoral and humoral TEPs (CD41+/CD62P+) was screened in luminal A (LumA) and triple negative (TNBC) BC subgroups. The impact of TEPs on lin-/CD44+/CD24- CSCs of both the categories in-vitro, was deciphered by performing mammosphere assay, clonogeneic and migration assays, with final validation in murine system. Effect on various genes and proteins related to stemness, metastasis and angiogenesis as a result of this interaction was elucidated by RT-PCR, flow cytometry and western blotting. Results: High percentage of TEPs in the peripheral blood is a potential biomarker and responsible for poor prognosis in BC subtypes. Both Lum A and TNBC patients had elevated TEP frequency, compared to healthy blood. Further, patients in the pre-carcinogenic stage had platelet count of >3.5 lakhs. Additionally, screening of breast tumor sections revealed intra-tumoral enrichment of TEPs, comparatively to a greater extent in TNBC than LumA, supporting their role in disease aggression. Also, a positive correlation was noted between TEP and CSC frequencies proving their synergistic interactions. Moreover, in-vitro, TEP influenced CSCs exhibited enormous clonogenic and tumorigenic potentialities. Their metastatic nature was confirmed by their enhanced migratory, invasive, angiogenic capacities with higher VIMENTIN and TWIST along with HIF1α, CD31 and MMP9 expression compared to E-CADHERIN. In line with in-vitro observations, in-vivo too, TEP~CSC produced metastatic colonies in murine lungs. Upon investigation, it was disclosed that it is through WNT-βcatenin-VEGFR2 axis that this mutual interdependency was functioning. Conclusions: This study advocates for the importance of TEPs as potential biomarker in BC diagnosis. Their alliance with vicious CSCs to promote disease advancement acquiesce them as a novel restorative agent.

AUTO-TUNE: selecting the distance threshold for inferring HIV transmission clusters.

Molecular surveillance of viral pathogens and inference of transmission networks from genomic data play an increasingly important role in public health efforts, especially for HIV-1. For many methods, the genetic distance threshold used to connect sequences in the transmission network is a key parameter informing the properties of inferred networks. Using a distance threshold that is too high can result in a network with many spurious links, making it difficult to interpret. Conversely, a distance threshold that is too low can result in a network with too few links, which may not capture key insights into clusters of public health concern. Published research using the HIV-TRACE software package frequently uses the default threshold of 0.015 substitutions/site for HIV pol gene sequences, but in many cases, investigators heuristically select other threshold parameters to better capture the underlying dynamics of the epidemic they are studying. Here, we present a general heuristic scoring approach for tuning a distance threshold adaptively, which seeks to prevent the formation of giant clusters. We prioritize the ratio of the sizes of the largest and the second largest cluster, maximizing the number of clusters present in the network. We apply our scoring heuristic to outbreaks with different characteristics, such as regional or temporal variability, and demonstrate the utility of using the scoring mechanism's suggested distance threshold to identify clusters exhibiting risk factors that would have otherwise been more difficult to identify. For example, while we found that a 0.015 substitutions/site distance threshold is typical for US-like epidemics, recent outbreaks like the CRF07_BC subtype among men who have sex with men (MSM) in China have been found to have a lower optimal threshold of 0.005 to better capture the transition from injected drug use (IDU) to MSM as the primary risk factor. Alternatively, in communities surrounding Lake Victoria in Uganda, where there has been sustained heterosexual transmission for many years, we found that a larger distance threshold is necessary to capture a more risk factor-diverse population with sparse sampling over a longer period of time. Such identification may allow for more informed intervention action by respective public health officials.

Subpopulation composition of PD-L1-positive lymphocytes in the primary tumour in luminal breast cancer patients

The relationship between the tumour and the microenvironment is of great interest because it may determine the efficacy of new agents aimed at targeting the anti-tumour immune response, such as immune checkpoint inhibitors (ICI s), which have been used to treat breast cancer. PD -L1 status in immune cells should be examined when prescribing ICI s for breast cancer. This highlights the importance of studying the characteristics of the tumour microenvironment, the main approach being to uncover its heterogeneity. The aim of this study was to investigate the subpopulation composition of PD -L1-positive lymphocytes in the tumour microenvironment, separately in each luminal subtype of BC, and to compare it according to the PD -L1 status of the tumour. Material and Methods. Fifty-two primary tumour samples were obtained from patients with invasive luminal A, luminal B HER2- and luminal B HER2+ subtypes of breast cancer (T1–2N0–1M0). No drug therapy was administered prior to surgery to any patient in this study. Cytotoxic lymphocytes (CTL s), B lymphocytes, T helper lymphocytes, T regulatory lymphocytes and their PD -L1 expression in tumour tissue samples were assessed by flow cytometry, and tumour PD -L1 status was determined by Ventana SP 142 immunohistochemistry. Results. All of the key lymphocyte populations we identified were present in almost all patients. The number of PD -L1-positive Th2 lymphocytes was significantly higher in the luminal A and luminal B HER2- BC samples compared to the luminal B HER2+ cases (р=0.0240 and p=0.0092, respectively). When the proportion of PD -L1-positive cells was calculated, the proportion of PD -L1-positive Th2 lymphocytes and T regulatory lymphocytes was significantly lower in luminal B HER2-compared to luminal A BC. Cytotoxic lymphocytes, Th2 lymphocytes and T-regulatory lymphocytes represented the predominant PD -L1-positive immune cells in the breast cancer microenvironment and were present in higher numbers in PD -L1-positive luminal B HER2-. Conclusions. Different lymphocyte populations, including those expressing PD -L1, can be found in the breast cancer microenvironment and there are differences in their numbers between different luminal breast cancers. This may explain the discordant prognostic and predictive value of the microenvironment in luminal breast cancer when considered as a single molecular subtype.

The prognostic value of lymph node response to neoadjuvant therapy among breast cancer subtypes

Objectives. The aim of this study was to assess the prognostic value of persistent node involvement after neoadjuvant chemotherapy among breast cancer subtypes. Materials and methods. A total of 258 patients with T1-T4 and N0-N3 breast cancer treated by neoadjuvant chemotherapy followed by tumor excision and axillary lymph-node dissection between January 2015 and December 2019 were selected from the Coltea Clinical Hospital database and retrospectively evaluated. Association between nodal involvement (ypN) binned into four classes (0, 1-3, 4-9 and >10), relapse free-survival and overall survival among the whole population and according to breast cancer subtypes was analyzed using Statistical Package for Social Science Version 29.0.2.0. Outcomes. After a median follow-up of 20.7 months (range 1-97 months) post neoadjuvant chemotherapy nodal involvement was significantly associated with disease free survival in the whole population (X2(3)= 23.161, p <.001) and between breast cancer subgroups (X2(3) = 27.871, p= <.001). After univariate cox regression analyses by breast cancer subtypes nodal involvement was statistically significant only in the Luminal B(HER-) (X2(3)=14.867, p=.002) and triple-negative breast cancer (X2(3)= 9.867, p=.020). In Luminal B(HER2-) breast cancers all nodal involvement subgroups were associated with impaired relapse free survival compared to ypN0 tumors (1-3 nodes, HR= 4.871, 95%CI [1.32-17.94], p=.017; 4-9 nodes, HR=5.126, 95%CI [1.341-19.59], p=.017; >10 nodes, HR=8.744, 95%CI [2.379-32.13], p=.001). In triple negative breast cancers, relapse-free survival was associated with an adverse prognosis in patients with more than 10 nodes involved when compared with ypN0 (HR=16.57, 95%CI [3.25-84.30], p=<.001). There was no statistically significant association in the univariate cox regression analyze between post neoadjuvant chemotherapy nodal involvement and overall survival neither in the whole population (X2(3)=.992, p=.803) nor among breast subtypes (X2(3)=1.191, p= .779). Kaplan Meier analyze of RFS adjusted for BC subtype showed a statistically significant relapse rate in all groups (1-3 (p=.035), 4-9(p=<.001), >10 (p=<.001)) compared with ypN0 group. Kaplan Meier overall survival analyze showed no statistical difference in survival among node groups. Conclusions. Post neoadjuvant chemotherapy lymph node status in breast cancer subtypes represents an important prognostic factor of relapse-free survival and the prognostic value of residual axillary disease should be interpreted according to breast cancer subtype.

A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy.

LBA500 Background: Prognosis of pts with early triple negative breast cancer (TNBC) is still poor and new effective treatments are needed. TNBC is the most immunogenic BC subtype, and this may account for sensitivity to immune checkpoint inhibitors. The A-BRAVE trial was designed to evaluate the efficacy of avelumab, an anti PD-L1 antibody, as adjuvant treatment for pts with early TNBC at high risk. Methods: This is a phase III, multicentric, randomized adjuvant study comparing 1 year of treatment with the anti PD-L1 avelumab vs observation for TNBC pts considered at high risk of relapse. Pts were enrolled after they completed standard treatment with curative intent including surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as: 1) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (Stratum A), 2) >pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (Stratum B). Pts were randomly assigned (1:1, balanced for strata A and B) to Avelumab 10 mg/kg I.V. q2w for 1 year or observation. Co-primary endpoints were disease free survival (DFS) in the total population and in Stratum A. 474 pts were needed to detect, in the total population, an improvement from 60% to 73.6% 3-year DFS rate (HR 0.6; 90% power, 1-sided test, alfa 2%). 172 DFS events were required to perform the event-driven analysis. Assuming a proportion of 70-80% pts enrolled in Stratum A, the expected power to detect an HR 0.6 at alpha allocated in this subgroup is 70-79%. Overall survival was a secondary endpoint. Results: From June 2016 to October 2020, 477 pts were randomly assigned from 64 Italian and 6 UK centers. 11 pts (3 avelumab, 8 control) withdrew consent immediately after randomisation and are excluded from further analyses. 378 pts entered Stratum A (83%), of whom 99 (57 avelumab, 42 control) received further chemotherapy after surgery prior to enrollment in the trial. Efficacy results for the two co-primary DFS endpoints and the secondary OS endpoints are reported in the table. Conclusions: One year adjuvant avelumab versus control does not significantly improve DFS in high-risk TNBC patients. Nevertheless, the secondary enpoind OS was significanlty improved with avelumab vs control. RFS and DMFS will also be reported. A centralised collection of tumor tissue, plasma and feces has been performed and will allow a number of correlative studies. Clinical trial information: NCT02926196 . [Table: see text]

Molecular network characteristics and drug resistance analysis of 392 newly reported MSM HIV/AIDS cases in Chongqing, China.

To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences of MSM to construct a phylogenetic tree and gene transmission network. Among the viral subtypes, CRF07_BC accounted for 73.2% (287/392) and CRF01_AE accounted for 20.7% (81/392), emerging as the predominant subtypes in this investigation. Additionally, we observed the presence of CRF55_01B, subtype B, CRF08_BC and other circulating recombinant forms. The HIV-1 molecular network was constructed with a gene distance threshold of 1.5%, resulting in an entry rate of 61.4% (241/392). Within the network, we identified a total of 23 molecular clusters, with the largest cluster being the CRF07_BC molecular cluster comprising 148 node values. Transmitted drug-resistance (TDR) mutations were found in 4.34% of the cases, with 1.79% associated with protease inhibitors (PIs), 0.51% with nucleoside reverse transcriptase inhibitors (NRTIs), and 2.55% with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Statistical analysis indicated a higher enrollment rate in the HIV-1 molecular network among infected individuals with the CRF07_BC subtype, those identifying with same-sex sexual roles as "vers," and individuals with higher education levels. This suggests the need for strengthened investigation and intervention in this population to prevent the formation of larger transmission clusters. Furthermore, continuous monitoring of the HIV-1 molecular dynamics network is necessary to promptly and accurately track changes in molecular epidemic characteristics.

The prevalence of sickle cell phenotype and its association with clinical outcomes in patients with solid malignancies.

10563 Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States and is caused by a mutation of β-globin ( HBB-Mt). The risk of developing solid malignancies in this population remains controversial, with research showing increased rates of some solid tumors (colon, kidney, and thyroid) and decreased rates of others (breast and male genitourinary). We report the prevalence of HBB mutations across a cohort of solid tumors and clinical outcomes between HBB-Wild type (-Wt) v Mutant (-Mt) tumors. Methods: Non-small cell lung cancer (NSCLC, N = 3307), breast (BC, N = 1960), colorectal (CRC, N = 2161), prostate (N = 899), and gynecologic cancers (N = 2,805) in persons of African descentwere tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole exome) and RNA (whole transcriptome). Her2/Neu (+: ≥3+ and >10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was tested by immunohistochemistry. Tumors were assessed for single nucleotide variations (SNVs) and insertions/deletions (indels) in HBB associated with a sickle cell phenotype. Mutation prevalence for all other genes was calculated for pathogenic SNVs/indels. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s Exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p < .05). Real-world overall survival (OS) and ethnicity data was obtained from insurance claims and log-rank estimates were calculated for molecularly defined subpopulations. Results: Amongst persons of African descent, uterine sarcoma had the highest prevalence of HBB-Mt (17.1%, 43/251) followed by uterine serous carcinoma (9.1, 70/768) and endometrial carcinoma (7.8, 55/708). Tumors with the highest absolute number of HBB-Mt tumors were NSCLC (7.0, 230/3307), CRC (8.1, 176/2161) and BC (6.7, 131/1960). In CRC, there was no significant difference in the prevalence of right-sided tumors between HBB-Wt v Mt (42% v 51, p = .06), nor in the prevalence of HBB-Mt by consensus molecular subtype ( p = .34). No significant enrichment of HBB-Mt across BC subtypes was observed (HR- HER2-: 7.8%, HR-HER2+: 9.7, HR+/HER2-:5.8, HR+/HER2+: 8.1, p = .34). No difference in the prevalence of pathogenic alterations was observed between HBB-Mt vs -Wt across NSCLC, CRC, and BC ( p > .05). HBB-Mt NSCLC were significantly enriched (GSEA) for genes related interferon /, inflammatory response and IL6/JAK/STAT3. No significant difference in OS was observed in CRC (median survival HBB-Wt: 957 days v -Mt: 1034, p = .43), NSCLC (-Wt: 591 v -Mt: 648, p = .59) or BC (-Wt: 924 v -Mt: 922, p = .61). Conclusions: No significant differences in the genomic landscape nor in OS of HBB-Mt vs HBB-Wt NSCLC, CRC or BC were observed. NSCLC HBB-Mt was enriched with inflammatory response genes. Future work should focus on potential role HBB-Mt plays in NSCLC.

Ki67 as a prognostic factor in male breast cancer (male BC): Results from a large GEICAM Spanish cohort of male BC.

556 Background: Male BC management is based, by default, on evidence produced from female BC. There is a high need to validate gender specific performance of established prognostic biomarkers. We present here descriptive results from a large, country specific, registry of Male BC. Methods: GEICAM/2016-04 (NCT03800355) is a retrospective, observational study including Male BC pts diagnosed from 2000 to 2019 in 51 Spanish sites. Data from BC diagnosis until 10-Mar-2020 was collected from medical charts; biological specimens were obtained. Pts and tumors characteristics, therapies, and outcomes were analyzed. Molecular subtypes were categorized as hormonal receptor positive (HR+)/HER2 negative (HER2−), triple negative (TN) (HR−/HER2−), and HER2+ (any HR). Results: 773 pts were analyzed, at first diagnosis, 721 (93%) had early BC (EBC) (stages I [28%], II [41%], III [21%]), and 52 (7%) de novo metastatic BC; median age was 66 (23-96) years; median body mass index was 28 (18-50) Kg/m2 (overweight), with obesity in 4% as prior medical history. Previous history of other cancers: 20 (3%) pts were diagnosed with prostate cancer (PC) and 20 (3%) pts with skin cancer (melanoma and non-melanoma). BC family history was reported in 212 (35%) pts, 56 (9%) PC, and 35 (6%) ovarian cancer. Germline genetic testing for hereditary risk was performed in 238 (31%) pts, with BRCA1/2 mutations present in 46 (19%) pts (BRCA1 in 6, BRCA2 in 39, and both in 1); BRCA1/2 mutations were observed in 9 (33%) HER2+ pts and 32 (18%) HR+/HER2− pts. Of EBC pts, 322 (45%) were node-positive, 274 (38%) had T2 tumors; 4% had breast conserving surgery, and 42% sentinel lymph node biopsy; 42% received adjuvant radiation therapy; 336 (47%) adjuvant and 44 (6%) neoadjuvant chemotherapy, 609 (84%) adjuvant endocrine therapy, mainly tamoxifen (72%); and 6% pts did not receive any systemic therapy. Morphologically, invasive carcinoma of no special type was reported in 89% pts, and 52% were grade 2. Per local pathological assessment, 97% estrogen receptor positive (ER+), 90% progesterone receptor positive (PgR+), 84% androgen receptor positive; 51% presented Ki67 index expression ≥20%, and 11% HER2+. Frequency according to molecular subtype: 599 (77%) HR+/HER2−, 75 (10%) HER2+, 6 (1%) TN, and 93 (12%) unknown. With a median follow-up of 64 months, medians of invasive disease-free survival (iDFS) and distant DFS (dDFS) were not statistically different in HR+/HER2− vs HER2+ pts and according to levels of Ki67 index expression (<20% vs. ≥20%). In a Cox multivariate model, stage I-II vs III and age were statistically significant (p<0.05) for both iDFS and dDFS. Conclusions: HR+/HER2− is the most common Male BC subtype, with ER and PgR highly positive, and 20% as median Ki67 index. No statistically significant differences were observed in terms of iDFS and dDFS based on level of Ki67 index expression. Clinical trial information: NCT03800355 .

Treatment patterns among HCPs and concordance with expert recommendations in HER2-negative early breast cancer: Analysis of an interactive online treatment decision support tool.

e13601 Background: Management of HER2- EBC continues to evolve with expansion of targeted therapies, including abemaciclib, olaparib, and pembrolizumab, in the adjuvant setting for eligible pts. We sought to identify contemporary practice patterns among HCPs for HER2- EBC and compare them with those of experts using an online interactive decision support tool. Methods: An online decision support tool was developed with input from 5 BC experts to provide tx recommendations for 19 unique pt case scenarios based on considerations including subtype, tx history, and recurrence risk. HCPs entered specific patient criteria along with their intended management for that case, and then were shown 5 expert recommendations. HCPs were asked if the recommendations impacted their intended approach. An analysis of expert recommendations and HCP-selected tx was performed. Results: Between Oct 2023 and Jan 2024, 83 HCPs entered 105 cases. Of the 97 cases where HCPs noted a definitive tx plan, recommendations were discordant from experts in 29%. The most commonly queried cases, expert recommendations, and discordance between HCPs and experts are outlined in the table. Discord with experts was similar among HCP tx plans for cases of TNBC (33%) and HR+/HER2- EBC (27%). HCPs predominantly sought guidance for pts with HR+/HER2- EBC, no g BRCAm, and high-risk disease per monarchE trial criteria (79%), with 22% discordance from expert recommendations. Regardless of BC subtype, the highest level of discord between HCPs and experts (67%) was observed in cases where pts had received neoadjuvant tx and had no residual disease following surgery, although this represents a small subset (n = 12). When asked if the expert recommendations changed their tx choice, 7 of 27 (26%) HCPs who responded indicated that expert recommendations changed their intended tx, whereas 15% noted that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges with incorporating the newest targeted therapies for high-risk EBC management. Continued education and development of resources for HCPs, including online decision support tools, may be increasingly important as the treatment of EBC continues to evolve. [Table: see text]

Retrospective observational study of patients with luminal breast cancer in early stages: 10-year follow-up—Which luminal breast cancer relapse?

e12586 Background: Luminal BC is a heterogeneous group of breast cancer (1), with molecular signatures of better prognoses and others of worse prognoses being found. Prosigna test provide the molecular BC subtype, an individualized prognostic score called “ROR score”. Our main objective is to analyze in 10 years which Luminal early BC patients have local and distant relapses. See if there is a correlation between ROR and relapse. As second objective is select this group of patients who relapse and analyze the presence of CAF S1 for a future study. Methods: We performed a retrospective observational study from the two main hospitals in Málaga (Spain) We included 415 women 43-79 years with EBC defined as T1 or T2 primary breast cancer <30 mm in the largest dimension) node negative. Molecular BC subtype analyzed by IHC and genomic platform Prosigna) The patients were treated with breast-conserving surgery with clear excision margins hypofractionated radiotherapy and adjuvant endocrine therapy. We followed them from 2014 to the present. Results: 415 patients. We made genetic platform Prosigna to all of them luminal A 55%, Luminal B 37%, Basal like 4.8% and Her2 3.6%. The median follow-up was 9.1 years. The cumulative incidence of recurrence in Luminal BC was 2.29% (44.4% locoregional 55.55% distant recurrence). In 55.55% of the patients that relapsed had a Prosigna test with high ROR score, in 11.11% of the patients that relapsed had a Prosigna test with an intermediate ROR score and in 33.33 of the patients that relapsed had a Prosigna test with a low ROR score. Conclusions: In our study the cumulative incidence of recurrence in Luminal BC was 2.29 % and the ROR score provided a good estimate of the risk of relapse. Currently we use genomic platforms as Prosigna to estimate the ROR and adapt treatments to the risk. However, until now there is no biological or translational study focusing on T1N0 luminal BC. Subsequently, there exists a real need for new strategies to determine the long-term prognosis of these patients. We selected a group of patients to analyze the presence of CAF S1 fibroblast for a future study. Distant recurrence in T1N0 Luminal BC is strongly associated with the presence of CAF-S1 fibroblast The determination of CAF-S1 could more accurately predict recurrence in this subgroup of patients and could be a target for future treatments.

HIV subtypes and molecular transmission characteristics among elderly HIV-infected individuals aged 50 and above: a cross-sectional study in Huzhou City, Eastern China

ObjectiveTo analyse the HIV-1 subtypes and molecular transmission characteristics of HIV-infected older individuals aged 50 and above in Huzhou City, and provide a scientific basis for prevention and treatment strategies...

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in < 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of < 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between < 40 and ≥ 50 y groups were performed. Results: Pts < 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were < 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ < 40y pts. The median time to recurrence was < 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( < 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of >2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both < 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-11.

Abstract PO5-24-11: An integrated approach for comprehensive molecular and tumor microenvironment characterization of invasive lobular carcinoma

Abstract Introduction: Although recent studies have shown that invasive lobular carcinoma (ILC) is associated with worse long-term outcomes compared to invasive breast cancer of no special type (NST), they are treated in a similar manner. Therefore, classification approaches to help understand the molecular characteristics associated with the different BC subtypes are needed to personalize therapy. Here, we describe an integrated analytical approach to comprehensively characterize ILC samples. Methods: We collected genomic and transcriptomic data for 16,087 ILC and NST samples, with clinical and pathological annotation, from 59 datasets and used an internally developed algorithm based on clustering performed after gene expression analysis to classify them into 5 intrinsic subtypes: Basal, Luminal A (LumA), Luminal B (LumB), HER2 high, and HER2 low. We performed gene set enrichment analyses and utilized the DESeq2 algorithm to perform differential expression analysis of RNA-seq data. We performed molecular grade subtyping using methods described by Antysheva et al. (Cancer Res., 2022). Samples that were listed as ILC or had an inactivated CDH1 gene by mutation, deletion or low expression (< −2.5 MAD after median scaling) were defined as having an ILC histomolecular subtype. Using methods described by Bagaev et. al. (Cancer Cell, 2021), 29 functional gene expression signatures were selected, and unsupervised dense Louvain clustering was performed to identify TME subtypes. The Mann-Whitney U test was used for statistical analysis. The tertiary lymphoid structures (TLS) gene signature was evaluated using methods described by Sautès-Fridman et al. (Nat. Rev. Cancer, 2019). Results: In the ILC samples (n=1,887), we identified LumA (46%), LumB (40%), Basal (8%,), HER2 high (3%), and HER2 low (3%) subtypes. In contrast, the NST samples were classified as LumB (41%), LumA (25%), Basal (19%), HER2 high (9%), and HER2 low (5%). Molecular grade subtyping revealed that 67% of ILC samples were low grade and 33% were high grade, compared to NST where 55% were high grade and 45% were low grade. Notably, among high-grade ILC, LumB (64%) and Basal (23%) subtypes were predominant. Key differentially expressed genes included downregulated CDH1 and upregulated MMP23B, IGF1, and TFAP2B across LumA and LumB ILC samples. Further analysis revealed downregulation of TACSTD2 and CDH3 in the Basal subtype for ILC samples compared to NST samples. Transcriptomic-based TME subtyping revealed distinct TME distributions across the BC subtypes and molecular grades for ILC samples (Table 1). In high-grade ILC LumB samples, 38% had a Desert (D; predictive of poor immunotherapy response) and 39% had an Immune-Enriched (IE; predictive of favorable immunotherapy response) TME. In low-grade ILC LumB samples we found that while 51% had a D TME, only 14% had an IE TME. We found an overrepresentation of the TLS signature [Solid TLS] in ILC compared to NST samples, and higher matrix remodeling and CAF signatures in LumA compared to the LumB subtype among low-grade ILC samples. Samples with high CD274 expression levels had higher percentages of T cells and M1 macrophages, and LumA samples had significantly higher (p < 0.001) CD274 expression compared to the other BC subtypes. Conclusion: These results provide in-depth molecular and tumor microenvironment characterization of ILC. Further optimization of this analytical approach could lead to the development of more effective therapeutic strategies. Table 1. ILC subtypes classification Citation Format: Jason Mouabbi, Konstantin Chernyshov, Oleg Baranov, Vladimir Kushnarev, Polina Turova, Anna Butusova, Sofia Menshikova, Jessica Brown, Nikita Kotlov, Patrick Clayton, Krystle Nomie, Nathan Fowler, Debu Tripathy. An integrated approach for comprehensive molecular and tumor microenvironment characterization of invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-11.

Abstract PO3-06-03: Overall Survival and Disease Interval Among Breast Cancer Subtypes in Patients with Brain Metastasis

Abstract Background: Breast cancer brain metastasis (bcbm) is associated with limited survival. There is a paucity of clinical trials and real-world data on the survival and disease interval [primary breast cancer (pbc) to metastatic breast cancer (mbc) or bcbm] of bcbm patients. We performed a retrospective study comparing the overall survival (OS) and disease intervals (INT) between the date of pbc surgery, diagnoses of mbc, and bcbm among 3 subtypes of bc in patients with bcbm. Methods: The informatics team generated a preliminary list of patients with a history of breast cancer and brain metastasis who were treated at the Wilmot Cancer Institute (WCI) of the University of Rochester. Key inclusion criteria were evidence of bcbm, bcbm diagnosed between Jan 1st, 2010 and June 1st, 2021, and adequate medical records available. Patients with de novo mbc were excluded. Final eligible patients were registered for the study. Median OS in bc subtypes was assessed with the Kaplan-Meier method and compared using the log-rank test. Median INTs among bc subtypes were compared using the Kruskal-Wallis test. Registered patients were divided into triple-negative (TNBC), estrogen receptor-positive/HER2 negative (ER+/HER2-), and HER2+ subtypes. Results: Out of 191 patients screened, 83 patients were eligible for the study. The total number of patients enrolled by subtype was 26 (TNBC), 35 (ER+/HER2-), and 22 (HER2+). Disease and patient characteristics are shown in Table 1. Median OS from pbc, mbc, and bcbm among 3 subtypes are shown in Table 2. The differences in the median OS from these 3 different time points were not statistically significant among 3 subtypes. After adjusting for important variables (age, race, tumor grade, stage, and presence of perioperative therapy) in a Cox regression model, there was still no statistical evidence that these 3 subtypes differed in OS. Three different INTs (pbc-mbc, pbc-bcbm, mbc-bcbm) among 3 subtypes are shown in Table 3. INTpbc-mbc and INTpbc-bcbm were significantly different among 3 subtypes of bc. After adjusting for the factors in the model, the subtypes didn’t differ significantly with respect to INTpbc-mbc and INTpbc-bcbm. Stage 3 at pbc was significantly associated with shorter INTpbc-mbc and INTpbc-bcbm. The distribution of INTmbc-bcbm was highly non-normal due to the high % of patients with concurrent diagnoses of mbc and bcbm. Thus an exploratory logistic regression model assessed the association of subtypes and important variables with the odds of having mbc and bcbm concurrently (INTmbc-bcbm< 1 month). It showed that the ER+/HER2- subtype had 4 times lower odds of concurrent mbc and bcbm diagnosis than the HER2+ subtype (p=0.03). In an unadjusted pairwise comparison between the subtypes (Table 3), the ER+/HER2- group had statistically longer INTpbc-mbc and INTpbc-bcbm than TNBC. However, when the subtypes were adjusted for Stage 3 vs 1 or 2, these subtypes were not significantly different for these INT. In our study, a higher proportion of Stage 3 tumors in TNBC subtype is likely associated with the shorter INTs seen with TNBC in unadjusted analysis. Conclusion: Adjusted comparison of OS and disease intervals from pbc between TNBC, ER+/HER2-, and HER2+ subtypes were not statistically different in this cohort of bcbm patients. Interestingly, median OS from mbc were numerically very similar (3.6-3.7 years) among these subtypes. Median OS from pbc and bcbm were numerically longer in HER2+ bc than the other 2 subtypes. Intervals between pbc to mbc and to bcbm and between mbc to bcbm were numerically longer in ER+/HER2- subtypes than the other 2 subtypes. ER+/HER2- subtype was 4 times less likely to have concurrent bcbm at the time of mbc diagnosis than the HER2+ subtype. These results are exploratory and hypotheses generating. Table 1: Disease and Patients Characteristics Table 2: Overall Survival Unadjusted Table 3: Disease Intervals Unadjusted Citation Format: Asis Shrestha, Sugam Gouli, Sujan Niraula, Ramandeep Babbra, Niraj Neupane, Sarah Stanford, Myla Strawderman, Zeni Kharel, Huina Zhang, Sara Hardy, Nimish Mohile, Carey Anders, David Hicks, Ruth O'Regan, Ajay Dhakal. Overall Survival and Disease Interval Among Breast Cancer Subtypes in Patients with Brain Metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-03.