Young Triple Negative Breast Cancer Research Articles

282P Impact of pembrolizumab on ovarian function in young triple negative breast cancer patients treated with chemo-immunotherapy

282P Impact of pembrolizumab on ovarian function in young triple negative breast cancer patients treated with chemo-immunotherapy

Abstract PO2-06-14: Kynurenine induces senescence reprogramming to promote metastasis in young triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC), which has been associated with a high risk of relapse and poor prognosis, has an increasing incidence among young women and ongoing inferior long-term outcomes. Given TNBC arising at a young age are more likely to present at advanced stages and to have aggressive biology, it is necessary to investigate the underlying mechanism and develop multidisciplinary strategies for optimal therapy of young women with breast cancer. Here, we integrated the multiomics data of our large TNBC cohort (n=456) to investigate different molecular mechanism between younger and older patients in the context of genetic and transcriptional subtypes and immune cell infiltration. We discovered that young TNBC patients exhibited a poorer outcome of both 2-year relapse-free survival and 2-year distant disease-free survival. Multi-omics analysis revealed that kynurenine (KYN) was preferentially enriched in young TNBC and activated tumor cellular senescence pathway which was positively correlated with increased metastasis. Mechanistically, KYN activated the aryl hydrocarbon receptor (AHR) signaling pathway in an ARNT2-dependent manner which was critical for cellular senescence, to mediate senescence reprogramming and promote tumor metastasis in young TNBC. Our findings unveil a novel interplay between cancer cell metabolites and cell senescence, which provides valuable insights that can potentially enhance therapeutic strategies for young TNBC patients. Keywords: young TNBC, metastasis, kynurenine, cellular senescence, AHR pathway Citation Format: Cui-Cui Liu, Ke-da Yu. Kynurenine induces senescence reprogramming to promote metastasis in young triple-negative breast cancer [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 PO2-06-14.

Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

BackgroundDue to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account.MethodsWe included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models.ResultsAmong the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7–65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29–7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19–0.95) incidence of second primary tumors, compared to BRCA1-non-alteration.ConclusionsAlthough both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.

Abstract 1451: BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) patients

Abstract Background: Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. To date, triple negative breast cancer (TNBC) shows substantial overlap with basal type cancer and it is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. In the present study, we screened for the prevalence of BRCA1 and BRCA2 germline mutations in a cohort of 169 TNBC patients using PCR-Sanger sequencing and NGS with a cancer panel of 30 hereditary cancer genes or BRCA1/BRCA2 genetic test. Materials and Methods: 169 TNBC patients and their relatives were referred trough several public hospitals from six years (2013-2019). BRCA1 germline mutation was screened using PCR-Sanger sequencing in 66 TNBC patients with strong family history of breast and ovarian cancer and 103 sporadic TNBC patients including all exons where a mutation was previously found in Algerian population (exons 2, 3, 4, 10, 17 and 19). BRCA2 germline mutation was screened using PCR-Sanger sequencing in 24 TNBC patients with strong family history of breast cancer including all exons where a mutation was previously found in Algerian patients (exons 10 and 22). In addition, nine (9) TNBC patients with strong family history of breast and ovarian cancer were analyzed by NGS using BRCA1 and BRCA2 test or a cancer panel of 30 hereditary genes (Colors genomics). Results: The analysis of the genomic DNA samples of 169 TNBC patients revealed that 15 patients carried pathogenic germline variants in BRCA1 gene and three patients carried pathogenic variants in BRCA2 gene (10.65%). Eight distinct germline mutations in BRCA1 have been detected in this study: c.83_84delTG, c.181T&amp;gt;G, c.798_799delTT, c.505C&amp;gt;T, c.923_924delGC, c.2125_2126insA, c.5257A&amp;gt;G and deletion of exon 15. Interestingly, the recurrent and specific mutation c.83_84delTG has been detected in 4 unrelated TNBC patients. The pathogenic variant c.2125_2126insA has been detected in three unrelated families and also in the first relatives of 2 patients. The rare likely pathogenic variant BRCA1 c.5257A&amp;gt;G/p.Arg1753Gly has been detected in young female TNBC patient. The Del exon 15 in BRCA1 has been detected in two unrelated patients. Three distinct germline mutations in BRCA2 have been detected in three TNBC patients: c.1813dupA, c.7654dupA and c.8485C&amp;gt;T. Interestingly, these three mutations are reported for the first time in Algerian population. The c.1813dupA and c.8485C&amp;gt;T pathogenic variants have been detected in two young female TNBC patients with a family history of male breast cancer. Conclusions: In the current study, we detected recurrent germline mutations in BRCA1 gene in early onset TNBC patients. BRCA2 pathogenic variants have also been detected in young female TNBC patients. TNBC immunophenotype should be considered as an additional criterion for genetic counselling and testing of BRCA genes in Algerian women with early onset breast cancer. Citation Format: Farid Cherbal, Chiraz Mehemmai, Hadjer Gaceb, Hassen Mahfouf, Kada Boualga. BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1451.

Correlation Between Intensity of Vimentin Immuno-expression in Young Women with Triple Negative Breast Cancer and Its Cliniocopathological Parameters.

Young breast cancer patients (≤40 years) have different unifying oncogenic signaling pathways when compared to older people. Vimentin is a filament intermediate. Vimentin expression has an important role in epithelial-to-mesenchymal transition (EMT) and cancer progression. The aim of this study was to assess the correlation between vimentin intensity and clinicopathological parameters in patients with triple negative breast cancer aged 40 years. Samples were taken from 45 paraffin blocks of patients with young woman with triple negative invasive breast cancer NOS type that met the inclusion criteria, immunohistochemical examination was performed with vimentin. Vimentin intensity was assessed using ImageJ analysis. Samples were taken from paraffin blocks of patients with triple negative invasive breast cancer NOS type that met the inclusion criteria, immunohistochemical examination was performed with vimentin. Vimentin intensity was assessed using ImageJ analysis. This study shows that vimentin intensity is strongly associated with tumor progression, tumor mass size and tumor invasion so that it can be used as a prognostic factor in young triple negative breast cancer patients.

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences.

Background: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. Methods: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census—CGC, the Candidate Cancer Gene Database—CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. Results: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67–83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20–35% TNBC (Y vs. E); DNA repair genes were mutated in 19–33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. Conclusion: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.

In vivo selection of the MDA-MB-231br/eGFP cancer cell line to obtain a clinically relevant rat model for triple negative breast cancer brain metastasis.

Young triple negative breast cancer (TNBC) patients are at high risk for developing very aggressive brain metastases associated with a poor prognosis and a high mortality rate. Preclinical models that allow follow-up by magnetic resonance imaging (MRI) can contribute to the development of new therapeutic approaches for brain metastasis. To date, preclinical brain tumor research has almost exclusively relied on xenograft mouse models. Yet, rats are an ideal model for imaging of brain metastasis as their larger brain offers better relative spatial resolution compared to a mouse brain. For the development of a clinically relevant rat model for TNBC brain metastasis, the MDA-MB-231br/eGFP cancer cell line can be used. However, as a result of species-dependent extracranial features, the propensity of the MDA-MB-231br/eGFP cancer cell line to metastasize exclusively to the brain needs to be enhanced by in vivo selection. In this study, repeated sequential passages of metastatic cancer cells obtained from brain metastases in nude rats were performed. Brain metastasis formation was evaluated using preclinical MRI, while bone metastasis formation was assessed using high-resolution computed tomography (CT) and 2-deoxy-2-[18F] fluoro-D-glucose ([18F] FDG) positron emission tomography (PET) imaging. Our results demonstrated that the metastatic tumor burden in the rat brain (number and volume) significantly increased with increasing passage, while the metastatic tumor burden in the skeleton (i.e., number of metastasis-affected bones) significantly decreased with increasing passage. However, bone metastasis development was not reduced to a negligible amount. Consequently, despite in vivo selection, our rat model is not recommended for investigating brain metastasis as a single disease. Our findings highlight the importance of well-reasoned selection of both the preclinical model and the cancer cell line in order to obtain reliable and reproducible scientific results.

159O Prognostic value of tumour infiltrating lymphocytes in young triple negative breast cancer patients who did not receive adjuvant systemic treatment; by the PARADIGM study group

159O Prognostic value of tumour infiltrating lymphocytes in young triple negative breast cancer patients who did not receive adjuvant systemic treatment; by the PARADIGM study group

Abstract P3-10-05: BRCA1/2 alterations are present at significant rates across breast cancer subtypes and are associated with a high genome-wide loss of heterozygosity signature

Abstract Background The recent approval of PARP inhibitor, olaparib, in HER2-negative breast cancer expands the therapeutic options for patients with germline BRCA1/2 alterations. The role of somatic BRCA alteration as a predictive biomarker in breast cancer is currently unclear. NCCN guidelines call for germline testing in all young patients (&amp;lt;46 yrs) and patients with triple negative breast cancer (TNBC) (&amp;lt; 61 yrs) with a personal history of breast cancer. Here we examined the landscape of BRCA mutations to assess whether additional populations may have potential benefit from PARP inhibitors. Methods Hybrid-capture based comprehensive genomic profiling of 395 cancer-related genes using the FoundationOne assay (Foundation Medicine, MA) was performed on 12,508 breast carcinomas. Somatic/germline/zygosity status for BRCA1/2 variants was analyzed as described in Sun, 2018 (PMID: 29415044). High genome-wide loss-of-heterozygosity (gLOH) was classified as ≥16% LOH. Subgroups were analyzed on histological {Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC)} and molecular subtypes [ER-positive (ER+), HER2-amplified (HER2+), TNBC], patient age [≤45, 46-60, 61+], and gender. Results Consistent with previous reports, the frequency of BRCA1/2 alterations was highest in young patients (&amp;lt;46; 15%), TNBC (10%), and male breast cancer (14%); BRCA1/2 alterations were also identified in HER2+, ILC, and ER+ tumors (5.3%, 6.5%, 8.3%). Overall, BRCA1 was more frequently mutated in TNBC and young patients (67%), whereas BRCA2 was more frequently mutated in ER+, HER2+, ILC, and male breast cancer (63%, 57%, 79%, 100%). The fraction of somatic BRCA mutations (sBRCA) was 38%, with the lowest fraction of sBRCA in TNBC and young patients (30%, 30% overall, 36%, 42% for BRCA1) and highest in HER2+, ILC, and older patients (46%, 52%, 51%); the absolute frequency of sBRCA is approximately 3.5%. In tumors with ESR1 mutations, we detected concurrent BRCA mutation in 6.4% (85/1319), with 48% predicted somatic. Almost all tumors with BRCA mutations had biallelic inactivation, with LOH of the second allele irrespective of predicted germline status (90% of gBRCA and 86% of sBRCA under LOH). gLOH score was used as a phenotypic measure of homologous recombination deficiency (HRD): patients harboring biallelic BRCA alterations had elevated rates of gLOH with 89% of gBRCA and 84% of sBRCA tumors harboring a high gLOH score, vs 47% with heterozygous BRCA, 34% with no BRCA alteration, and 80% for patients with BRCA deletion. Conclusions Thirty-eight percent of deleterious BRCA alterations in breast are predicted somatic, including 36% of BRCA1 alterations in TNBC. Germline testing would miss these alterations even though they are frequently under LOH and are associated with high gLOH, a biomarker with predictive value in ovarian cancer. While patients with ER+ and HER2+ tumors have low rates of gBRCA alterations, the overall BRCA mutation rate, including somatic alterations, is appreciable at 8.3% and 5.3%. Our findings demonstrate that sBRCA alterations are associated with a comparable HRD phenotype to gBRCA altertions and suggests that PARP inhibitors may have potential value for a wider range of breast cancer patients. Citation Format: Sokol ES, Frampton GM, Ross J, Ali S, Chung J, Oesterreich S. BRCA1/2 alterations are present at significant rates across breast cancer subtypes and are associated with a high genome-wide loss of heterozygosity signature [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-05.

PO-347 sONE, a novel tumour suppressor lncRNA, with diminished expression level in young triple negative breast cancer (TNBC) patients with lymphnode metastasis and large tumour size

IntroductionA recent surveillance of the human transcriptome has highlighted a pivotal class of RNA known as long non-coding RNA (lncRNAs). Myriad studies have reported the vital role of lncRNAs in oncology. However, the field is still in its infancy. lncRNAs are expressed in a highly cancer type-specific manner, thus could hold a lot of promises for personalised cancer therapy. In 2015, sONE has been identified as a novel lncRNA that acts as a post-transcriptional regulator of endothelial nitric oxide synthase (NOS3) expression in cultured endothelial cells. However, the role of sONE has never been investigated in any type of malignancy including Breast Cancer (BC). Among BC patients, TNBC is associated with the worst prognosis especially in young women (<40 years old). Young TNBC patients exhibit the most aggressive behaviour of tumours. Recently, few studies have been dedicated to identify actionable targets to this hard-to-treat group of patients. Therefore, our aim is to evaluate the expression pattern of sONE and its down-stream target (NOS3) in TNBC patients and to validate the role of sONE/NOS3/NO signalling cascade in TNBC cell linesMaterial and methodsBreast tissues were collected from 70 BC patients. Ki67 levels were quantified using immunohistochemistry. Clinical data of all patients were collected. MDA-MB-231 human BC cell lines were transfected using different oligonucleotides. Total RNA was extracted and quantified using qRT-PCR. NO production was assessed using Greiss reagent method. Cellular viability and proliferation were measured using MTT, BrdU assays, respectivelyResults and discussions sONE was significantly down-regulated in TNBC patients compared to its normal counterparts. Within TNBC patients, young females showed a diminished expression level of sONE. Furthermore, sONE expression pattern was inversely correlated with tumour size and lymph node metastasis in young TNBC patients. Our results showed that NOS3 expression level was reciprocally up-regulated.On the molecular level, sONE siRNAs resulted in an increase in NOS3 levels and NO production in MDA-MB-231. On the functional level, knocking down of sONE levels resulted in a significant increase of cellular viability and cellular proliferation rates of MDA-MB-231ConclusionThis study highlights a novel prognostic value of sONE in young TNBC patients where sONE expression level was negatively correlated with the aggressiveness of the disease. Moreover, this study validated sONE/NOS3/NO as a novel tumour suppressor signalling axis in BC patients.

Prognostic role of adjuvant radiotherapy in triple‐negative breast cancer: A historical cohort study

The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0-94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.