Triple Negative Carcinoma Research Articles

A phase I/II study of C019199 in combination with sintilimab in advanced malignancy.

e15110 Background: C019199 is an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor and modulates the immune micro-environment of tumor cells. Previous phase I study of C019199 as a mono-therapy for advanced solid tumors has shown promising safety and anti-tumor activity. This phase I/II study is to evaluate the safety and efficacy of the combination of C019199 and Sintilimab in solid tumors. Methods: An open label, multicenter phase I/II study of C019199 combined with Sintilimab is currently enrolling (NCT06220318). Eligible subjects (age of ≥18 years and <76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. This trial consists of 2 parts: a phase I dose escalation study using a standard 3+3 design with 3 doses of C019199 (100 mg/qd, 200 mg/qd, 300 mg/qd) combined with a fixed dose of Sintilimab (200 mg, iv, q3w) to determine the maximum tolerated dose (MTD) and recommended phase Ⅱ dose (PR2D); A phase II study is planned to enroll about 20 patients in each tumor type, including but not limited to the following: colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, pancreatic cancer, triple negative breast cancer, head and neck squamous cell carcinoma. Results: A total of 10 patients with advanced solid tumors were enrolled in the phase I study from Jul 20, 2023 to Nov 14, 2023. Median age was 54 (range, 37-71), with 6 males and 4 females. Tumor types were colorectal cancer (7 pts), non-small cell lung cancer (2 pts) and cervical cancer (1 pts), with a median 3 prior systemic therapies (range, 1-7). As of Jan 15, 2024, we have assessed safety in all pts and efficacy in pts with at least one tumor assessment result. No dose-limiting toxicities (DLT) observed in the dose range of 100 mg/qd~300 mg/qd and the MTD has not been reached. The most frequently reported TRAEs were aspartate aminotransferase increased (80%), γ-glutamyltransferase increased (70%), proteinuria (70%), creatine kinase-MB increased (70%), alkaline phosphatase increased (60%). Grade ≥3 TRAEs were hypertension (30%), proteinuria (10%), immune hepatitis (10%), diarrhea (10%). Among 7 colorectal cancer patients, 1 subject had partial responds (PR) and 6 had stable disease (SD) as the best responds with ORR of 14.3%, DCR of 100%. Four subjects were still on treatment. Median PFS was not reached (>3month). Two patients with non-small cell lung cancer and 1 patient with cervical cancer achieved the best response of SD, with a DCR of 100%. Phase II study is ongoing. Recommended dose is 200 mg/qd as the RP2D in selected solid tumors. Conclusions: The combination of C019199 and Sintilimab has shown good overall safety and tolerability. No DLT was observed in the dose range of 100 mg/qd ~ 300 mg/qd. Preliminary anti-tumor activity was observed in patients with advanced solid tumors. Phase II study is ongoing to accumulate more clinical data. Clinical trial information: NCT06220318 .

Fusogenic vesicular stomatitis virus combined with natural killer T cell immunotherapy controls metastatic breast cancer

BackgroundMetastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models.MethodsUsing primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells.ResultsTreatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge.ConclusionCombining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer.

Abstract PO5-17-02: Triple-negative breast cancer as an untraceable tumor compared to other immunohistochemical subtypes: a cross-sectional study

Abstract Objective: To compare the form of presentation at diagnosis of triple negative breast tumors with other immunohistochemical subtypes, in relation to clinical examination or imaging examination. Methods: This is a cross sectional study that evaluated data related to the presentation of breast carcinomas at diagnosis (clinical examination or screening imaging examination findings), immunohistochemical subtype, histological grade and tumor size, in diagnosed and referred patients. for the Mastology service at Hospital São Paulo – Unifesp, in São Paulo – Brazil, in the period between 2012 and 2021, by analyzing data from the medical records of these patients. Results: Among the 699 invasive carcinomas diagnosed, 246 patients were diagnosed with luminal profile A (35.2%), 257 luminal B (36.8%), 58 luminal B HER-2+ (8.3%), 26 HER-2 enriched (3.7%) and 112 triple negative (16%). Triple negative carcinomas had a higher rate of diagnosis by clinical examination (86.6%), 6.65 times more likely to be diagnosed by clinical examination than luminal A, in addition to having a larger lesion. The triple negative and HER-2 enriched subtypes presented the worst scenarios of clinical stage at diagnosis. Among the tumors diagnosed by screening examination, those belonging to the luminal A were associated with nodules seen on imaging (in 45.1%) and the subtypes luminal B and luminal B HER-2+ with the appearance of microcalcifications. There were no cases of triple negatives involving microcalcifications in our sample. Asymmetries were more common in images of luminal B HER-2+ tumors. In the multivariate analysis, it was observed that only the histological grade and the Ki-67 value are related to the form of diagnosis. Tumors with histological grade 2 or 3 are more likely to be diagnosed by clinical examination and not be traceable in relation to histological grade 1. As for Ki-67, its increase of 1 percentage point leads to an increase of 1.3% in the chance finding on physical examination. There was no correlation of hormone receptors and HER-2 with the chance of the tumor not being screenable. Conclusions: triple negative subtype breast carcinomas present a higher risk of diagnosis by clinical examination compared to other immunohistochemical subtypes and, therefore, tend not to be traceable. Parameters such as high Ki-67 and histological grade correlate with this trend. Citation Format: Morgana Silva, Afonso Nazário, Vanessa Sanvido. Triple-negative breast cancer as an untraceable tumor compared to other immunohistochemical subtypes: a cross-sectional 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 PO5-17-02.

Abstract PO1-20-08: Primary breast implant-associated squamous cell carcinoma with subsequent TEMPUS testing and failure of immunotherapy

Abstract Primary squamous cell carcinoma of the breast is a rare entity, and there are a limited number of cases in the literature describing squamous cell carcinoma arising from breast implants. It has been hypothesized that these implant-associated cancers may arise from epithelialization of the implant capsule followed by chronic inflammation. None of the cases in the literature were treated with immunotherapy. We present a case of an aggressive, primary sarcomatoid squamous cell carcinoma of the breast arising from a breast implant that was treated unsuccessfully with simultaneous chemotherapy and immunotherapy following TEMPUS testing. Introduction: Breast augmentation is the most common plastic surgery procedure performed worldwide, with more than 300,000 done in the United States every year. While breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is extensively discussed in recent literature, other breast implant-associated cancers are rarer and less studied. Breast implant-associated squamous cell carcinoma (BIA-SCC) specifically is an extremely rare complication of breast augmentation and no guidelines for treatment exist. The American Society of Plastic Surgeons (ASPS) released a statement on BIA-SCC on 9/2022 following a safety communication from the FDA, and it is recommended health care providers submit case reports of BIA-SCC to a patient registry. Case study: We present the case of a female patient who underwent bilateral breast augmentation in 2006 with Mcghan textured, pre-pectoral, areolar saline implants. In 2022, she presented with swelling and a lump in her breast and underwent bilateral breast implant removal with capsulectomy. Pathology showed triple negative sarcomatoid squamous cell carcinoma of the right breast capsule. TEMPUS testing on the breast biopsy revealed a PIK3CA mutation and PD-L1 negative status. Her case was discussed with a multi-disciplinary team including plastic surgery, multiple oncologists, and radiation oncology and her clinical picture was determined to be most consistent with BIA-SCC. Based on the KEYNOTE-522 study, she was determined to be a candidate for neoadjuvant therapy with pembrolizumab and chemotherapy as she was newly diagnosed, previously untreated, nonmetastatic, and had a triple negative tumor. She received two cycles of carboplatin, paclitaxel, and pembrolizumab but unfortunately rapidly progressed with chest wall extension, multiple new pulmonary nodules, worsening lymphadenopathy, right ventricular tumor thrombus, and new malignant pleural effusion and was transitioned to hospice. Discussion: Seven cases of BIA-SCC, one case of squamous cell carcinoma (SCC) after liquid silicone injection augmentation, one case of squamous metaplasia on the breast implant capsule, and one case of epithelization of the breast implant capsule have been previously described in the literature (Table 1). None of the available cases of BIA-SCC report TEMPUS testing, and none of the patients were treated with immunotherapy. The origin of BIA-SCC is unclear, but several theories have been described including chronic inflammation leading to conversion of epithelial tissue on the capsule to SCC. It is unknown how the breast implant capsule might become epithelialized to begin with – introduction of epithelium intraoperatively during augmentation, rupture of epidermal cysts, existence of epithelium in the area from a childhood injury or from birth, or epithelization from chronic shear forces from the augmentation or leakage of the implant are all possibilities. With the ongoing data gathering through the FDA patient registry, we will continue to learn more about these rare cancers and potentially get further insight into their origins. Table 1 An overview of cases of BIA-SCC in the literature Citation Format: Emily Podany, Katherine Clifton. Primary breast implant-associated squamous cell carcinoma with subsequent TEMPUS testing and failure of immunotherapy [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 PO1-20-08.

Abstract PO2-17-10: Metaplastic breast cancer: description of 16 cases treated at a reference center and review of the literature

Abstract Background: Metaplastic breast carcinomas (MBC) are very rare and represent less than 1% of all invasive breast carcinomas. It is a heterogeneous neoplasm characterized by a mixture of adenocarcinoma with other histological elements such as squamous cells, spindle cells or other mesenchymal differentiation. Most MBC are hormone receptor and Her2 negative and tend to have a worse prognosis when compared to triple negative carcinomas. Clinically, they manifest as a rapidly growing palpable mass, without necessarily involving lymph nodes. According to the nomenclature of the WHO Classification of Tumors of the Breast (2012), tumors were classified into 4 variants: spindle cell, squamous cell, mesenchymal and mixed. Since publications on MBC are scarce in the literature, we studied the cases that were attended at Hospital Pérola Byington in the period 2010-2021. Methods: A retrospective study was carried out by reviewing the medical records of patients treated at the Reference Center for Women's Health - Pérola Byington Hospital, São Paulo, Brazil. Patients with breast cancer, with anatomopathological result confirming the diagnosis of metaplastic carcinoma were reviewed. Clinical data and histopathological characteristics were evaluated, as well as the type of treatment performed and the evolution. Results: A total of 16 female patients diagnosed with MBC were included. The median age was 56 years (ranging from 34 to 88). The mean initial size observed was 7 cm (ranging from 2 to 20 cm) and 94% of patients presented with a palpable mass. The initial clinical staging were I (12%), II (32%), III (50%) and IV (6%). The most common histological subtype was spindle cell (50%), of which 2 were squamous (12%), 3 mesenchymal (20%), 1 mixed spindle/squamous (6%) and 2 were not classified. Regarding immunohistochemistry, 14 patients (88%) had hormone negative and Her2 negative (triple negative). Of the 16 cases, 8 underwent mastectomy and 6 partial mastectomiy and 2 patients did not undergo surgical treatment because they died despite treatment with neoadjuvant chemotherapy. All operated patients underwent sentinel lymph node biopsy or axillary dissection and 85% of them did not have axillary lymph node involvement. Radiotherapy was indicated in 13 patients. Chemotherapy was performed in 10 patients, 6 of which were neoadjuvant (since the tumors were not resectable) and 4 received adjuvant chemotherapy. Of the 6 patients that underwent neoadjuvant chemotherapy, 2 had disease progression, 3 partial response and 1 complete pathological response. During follow-up, 4 (25%) evolved with locoregional recurrence and 5 (31%) with metastatic disease. Of these women, 44% (7) are still alive. We also found that 6 of the 16 cases (37%) did not receive a diagnosis of MBC in the initial biopsy, requiring revision, a new biopsy or study of the surgical specimen for confirmation. Conclusion: As verified in the literature, MBC is a very rare histological type and corresponded to 0.2% of all cases of breast cancer in the period described above. Most patients have an advanced tumor at the time of diagnosis and little axillary involvement. The most common histological classification is the spindle cell variant and almost all tumors are triple negative. The CMM has an aggressive behavior and little response to chemotherapy treatments. Therefore, radical surgical treatments are preferred. Due to the rarity of this entity there is little data published in the international literature. Citation Format: Andre Mattar, Marcelo Antonini, Marina Diogenes, Andressa Amorim, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. Metaplastic breast cancer: description of 16 cases treated at a reference center and review of the literature [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 PO2-17-10.

Abstract 7037: Comprehensive molecular and immune profiling of triple negative invasive lobular carcinoma

Abstract Background: Triple-negative invasive lobular carcinoma (TN-ILC) is a rare (0.1-1.4%) breast cancer with prognosis worse than ER positive ILC. Currently there are no targeted therapies or clinical trials specifically for TN-ILC. A comprehensive analysis of the molecular and immune landscape can help identify novel targets and pathways for TN-ILC to improve patient outcomes. Here, we characterized the molecular and immune signature of TN-ILC. Methods: 11,760 breast cancer samples (Invasive ductal (ID) TNBC, n=364; TN-ILC, n=31) were analyzed (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB) was tested by NGS. Microsatellite-instability (MSI) was tested by NGS. Immune cell fractions were calculated by deconvolution of WTS. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: TN-ILC had higher frequency of CDH1 (0.83% vs. 66.67%), ERBB2 (0.84% vs.28.57%), ARID1A (1.65% vs. 23.33%), CBFB (0.55% vs.16.67%), AKT1 (2.22% vs.16.13%) and KMT2C (3.83% vs.13.79%), but lower frequency of TP53 (89.7%5 vs. 38.71%) mutations (all p<0.05) compared to ID-TNBC. TN-ILC had higher frequency of TMB high (23.3% vs. 5.2%, p<0.05) but there was no difference in dMMR/MSI-H (0% vs 1.1%, p=1). TN-ILC had higher AR RNA (FC: 14.2), protein expression (80.6% vs. 24.8%) and higher frequency of fusion variant-AR (16.1% vs 4.9%) (all p < 0.05) compared to ID-TNBC. Analysis of inferred immune cell infiltrates showed that TN-ILC had higher infiltration of M2 macrophages (5.34% vs. 2.94%) and neutrophils (4.83% vs. 2.65%) but lower infiltration of M1 macrophages (3.46% vs 2.17%) and CD8 T cells (0.58% vs. 0.11%) (all p<0.05). TN-ILC had lower T cell inflamed signature (16.1% vs 35.7%, p<0.05), decreased immune checkpoint genes (CD274, CTLA4, FOXP3, LAG3, IDO, FC: 1.2-2.7, all p < 0.05), PD-L1 protein expression (SP142: 30.4% vs. 50.2%, p=0.06; 22c3: 15.4% vs. 42.6%, p = 0.05) and differential expression of BCL2 family genes (upregulation: BIK, FC: 2.2; downregulation: BAX, BAK1, BID, PMAIP1, MCL1, BCL2A1, BCL2L10, FC: 1.0-6.3, all p < 0.05) compared to ID-TNBC. Conclusion: These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed. Results of our study need to be validated in larger studies with survival correlation. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Jose Leone, Priya Jayachandran, Stephanie Graff, Mathew Oberley, George Sledge, Asher Chanan-Khan. Comprehensive molecular and immune profiling of triple negative invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7037.

Multifaceted antineoplastic curative potency of novel water-soluble methylimidazole-based oxidovanadium (IV) complex against triple negative mammary carcinoma

A bunch of complexes harboring vanadium as metal centers have been reported to exhibit a wide array of antineoplastic properties that come under non‑platinum metallodrug series and emerge to offer alternative therapeutic strategies from the mechanistic behaviors of platinum-drugs. Though antineoplastic activities of vanado-complexes have been documented against several animal and xenografted human cancers, the definite mechanism of action is yet to unveil. In present study, a novel water soluble 1-methylimidazole substituted mononuclear dipicolinic acid based oxidovanadium (IV) complex (OVMI) has been evaluated for its antineoplastic properties in breast carcinoma both in vitro and in vivo. OVMI has been reported to generate cytotoxicity in human triple negative breast carcinoma cells, MDA-MB-231 as well as in mouse 4T1 cells by priming them for apoptosis. ROS-mediated, mitochondria-dependent as well as ER-stress-evoked apoptotic death seemed to be main operational hub guiding the cytotoxicity of OVMI in vitro. Moreover, OVMI has been noticed to elicit antimetastatic effect in vitro. Therapeutic application of OVMI has been extended on 4T1-based mammary tumor of female Balb/c mice, where it has been found to reduce tumor size, volume and restore general tissue architecture successfully to a great extent. Apart from that, OVMI has been documented to limit 4T1-based secondary pulmonary metastasis along with being non-toxic and biocompatible in vivo.

Breast Carcinoma With Tubulopapillary Features Has a Distinct Immunophenotypic and Molecular Signature: A Report of Two Tumors and Literature Review.

Breast carcinoma with tubulopapillary features is a newly described entity associated with poor prognosis with only 14 tumors reported in the literature. We report 2 additional tumors and identify novel immunohistochemical and molecular features of the tumor. The first tumor was from a 72-year-old woman with nonmetastatic breast carcinoma and the second was from a 32-year-old woman with metastatic breast carcinoma who received neoadjuvant therapy. Both tumors had high-grade nuclear features with a distinctive morphology characterized by infiltrating open glands with intratubular papillary and micropapillary projections in >90% of the invasive carcinoma. In addition to the usual predictors of aggressive behavior, both tumors showed a high expression of p16 and SOX10, which has not been previously described. Targeted tumor sequencing revealed pathogenic variants of TP53 in both tumors, in agreement with previous reports. Prior studies have shown a correlation between p16 and SOX10 expression with high-grade features and worse prognosis; typically seen in triple-negative carcinomas as demonstrated in both of our tumors. However, not all reported tumors of breast carcinoma with tubulopapillary features have demonstrated a triple-negative profile as there are a few reports of tumors with estrogen receptor and/or human epidermal growth factor 2 expression. Due to their distinct morphologic and molecular characteristics, breast carcinoma with tubulopapillary features may represent a new breast cancer histologic subtype.

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) neutralization counteracts T cell immune evasion in breast cancer

BackgroundNicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that participates in nicotinamide adenine dinucleotide (NAD) homeostasis as well as a released cytokine (eNAMPT) that is elevated in inflammatory conditions and...

Immunohistochemical Staining Characteristics of Low-Grade Invasive Ductal Carcinoma Using the ADH5 Cocktail (CK5/14, P63, and CK7/18): A Potential Interpretative Pitfall.

Background: In our practice, the antibody cocktail ADH5 (CK5/14, p63, and CK7/18) helps with diagnostic challenges, such as identifying microinvasion and foci of invasive carcinoma, differentiating atypical ductal hyperplasia from hyperplasia of the usual type, and distinguishing basal phenotypes in triple-negative carcinomas. However, the ADH5 cocktail does have pitfalls and caveats. Methods: We describe our experience with the ADH5 cocktail of antibodies in breast pathology. Institutional knowledge and a literature search form our data sources. Results: We analyzed 44 cases. Four out of a total of 44 cases (9.1%)-two tubular carcinomas and two low-grade invasive breast carcinomas of no special type (ductal) with tubular features-showed an expected pattern of staining for ADH5 with a loss of brown (P63, CK5/14) staining around invasive glands and diffuse red (CK7/18) expression. Forty out of 44 (90.9%) cases showed an unexpected staining pattern (mixture of cytoplasmic brown and red). All 44 cases (100%) showed negative myoepithelial staining around invasive foci when separately stained for P63 and SMMH (Smooth Muscle Myosin Heavy). Conclusions: The unexpected staining pattern of ADH5 in low-grade invasive ductal carcinomas can be challenging to interpret in these lesions with low-grade cytology. The occurrence can cause confusion among users who employ multiplex stains, and it is important for users to be aware of this potential pitfall.

Invasive Carcinoma With Skin Adnexal Trichilemmal Hair Follicular Differentiation Occurring in the Breast: A Case Report With Detailed Immunohistochemical and Molecular Analysis.

Cutaneous-type adnexal tumors involving the breast are rare and create a diagnostic dilemma as they are often indistinguishable from primary mammary neoplasms. Tumors showing hair follicular differentiation are particularly challenging due to their rarity and the subtle appreciation of the intricate microanatomy of the hair follicle. We report a triple negative cutaneous-type adnexal carcinoma with follicular differentiation involving the breast to bring attention to the existence of these specialized group of tumors which should be managed differently from conventional triple negative carcinomas of the breast.

Genomic characteristics of triple negative apocrine carcinoma: a comparison to triple negative breast cancer.

Apocrine carcinoma is a rare breast cancer subtype. As such, the genomic characteristics of apocrine carcinoma with triple negative immunohistochemical results (TNAC), which has been treated as triple negative breast cancer (TNBC), have not been revealed. In this study, we evaluated the genomic characteristics of TNAC compared to TNBC with low Ki-67 (LK-TNBC). In the genetic analysis of 73 TNACs and 32 LK-TNBCs, the most frequently mutated driver gene in TNAC was TP53 (16/56, 28.6%), followed by PIK3CA (9/56, 16.1%), ZNF717 (8/56, 14.3%), and PIK3R1 (6/56, 10.71%). Mutational signature analysis showed enrichment of defective DNA mismatch repair (MMR)-related signatures (SBS6 and SBS21) and the SBS5 signature in TNAC, whereas an APOBEC activity-associated mutational signature (SBS13) was more prominent in LK-TNBC (Student's t test, p < 0.05). In intrinsic subtyping, 38.4% of TNACs were classified as luminal A, 27.4% as luminal B, 26.0% as HER2-enriched (HER2-E), 2.7% as basal, and 5.5% as normal-like. The basal subtype was the most dominant subtype (43.8%) in LK-TNBC (p < 0.001), followed by luminal B (21.9%), HER2-E (21.9%), and luminal A (12.5%). In the survival analysis, TNAC had a five-year disease-free survival (DFS) rate of 92.2% compared to 59.1% for LK-TNBC (P = 0.001) and a five-year overall survival (OS) rate of 95.3% compared to 74.6% for LK-TNBC (P = 0.0099). TNAC has different genetic characteristics and better survival outcomes than LK-TNBC. In particular, normal-like and luminal A subtypes in TNAC have much better DFS and OS than other intrinsic subtypes. Our findings are expected to impact medical practice for patients diagnosed with TNAC.

Germline BRCA 1 Positive Breast Ovarian Cancer Syndrome

Background: BRCA1 (Beast Cancer gene 1) and BRCA2 (Breast Cancer gene 2) are genes that produce proteins that help repair damaged DNA. Mutations in these genes predispose the person to a substantiable risk of developing breast and ovarian cancers among others. Approximately 10 to 15% of all cases of epithelial ovarian cancer and les than 10 % of Breast cancers are caused by a mutation in the BRCA1 or BRCA2 genes, which when occurs together results in hereditary breast ovarian cancer syndrome. Case Presentation: This case report presents the clinical course of a 57-year-old female patient who presented with a mass in her right breast in June 2022. The patient’s past medical history is significant with a diagnosis of triple-negative non-metastatic left breast cancer that was treated with surgery followed by adjuvant chemotherapy containing Doxorubicin and Taxanes with loco-regional radiotherapy in May 2009. On June 2022 (later after 13 years) patient noticed a Rt breast mass and was evaluated further. A mammography showed an ill-defined micro lobulated lesion 4 cm from the nipple, measuring 43 x 27 mm with a few microcalcifications. Later, an ultrasound right breast confirmed the presence of an ill-defined lesion in her right breast with no significant axillary nodes, True-cut biopsy performed on October 26th, 2022 revealed invasive triple negative ductal carcinoma. Staging work up with Positron Emission tomography and computerized tomography scan showed in addition to the right breast mass, an ovarian mass with peritoneal deposits. This prompted a peritoneal biopsy which confirmed a high grade primary serous carcinoma of ovary. Additionally, BRCA1/2 germline testing showed a positive BRCA1 germline mutation. Following this, the patient was started on neoadjuvant keynote 522 protocol specifically with Epirubicin, Cyclophosphamide, Paclitaxel carboplatin with pembrolizumab. As of the date of reporting she has completed CARBOPLATIN-TAXOL and is now on the third ........

Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.

Tall Cell Variant of Invasive Papillary Breast Carcinoma.

Tall cell variant of invasive papillary breast carcinoma is exceedingly rare, with only 30 cases reported in the literature. This report describes a case of a 47-year-old woman who presented to the clinic with bilateral breast masses on a screening mammogram. The patient was lost to follow-up, but she presented again after 4 years when the right breast mass significantly grew in size over several months. Mammography showed a 1.9 cm right breast mass and a 2.3 cm left breast mass. Ultrasound-guided core biopsy revealed right breast triple negative invasive carcinoma of the tall cell papillary variant and left breast fibroadenomatoid nodules. She underwent bilateral lumpectomies with a right sentinel lymph node biopsy and was started on chemotherapy after surgical excision.

GATA Binding Protein 3 (GATA-3) expression evaluation as prognostic factor in breast cancer and its relationship with other immunemarkers.

Breast cancer is the most frequent cancer in which the mortality rate could be decreased by proper management. The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. We studied the immunohistochemical (IHC) expression of estrogen and progesterone receptor, human epidermal growth factor receptor 2, and GATA-3 in 166 radical/partial mastectomy specimens having different histologic grades and stages of breast carcinoma. All samples were obtained from the pathology department of Sina hospital in Tehran-Iran from 2010 to 2016. There was a direct relationship between the luminal subtype carcinoma and higher GATA-3 expression (P-value: 0.001) and between triple-negative carcinoma and lower GATA-3 expression (P-value: 0.001). Moreover, there was a direct relationship between the metastasis rate and the tumor's grade with GATA-3 staining (P-value: 0.000 and 0.001, respectively). GATA-3 expression is related to the histopathologic and prognostic factors. GATA3 can be introduced as an important predictor in breast cancer patients.

Abstract P2-21-07: Exploring spatial correlations in Breast invasive Lobular Carcinoma subtypes using a novel CAF multiplex immunofluorescence panel

Abstract Background: Recent advances in immunotherapy led to development of new technologies to identify topographical distributions and correlations in the tumor microenvironment, enabling a better understanding of the tumor immune landscape. Based on the 2019 WHO classification Invasive lobular carcinoma (ILC) has various histological presentations. The pleomorphic variant has been reported to be biologically different to the classical counterpart. Cancer associated fibroblasts (CAFs) secrete cytokines and growth factors aiding in tumor growth. CAFs have been shown to express alpha-smooth muscle actin (α-SMA), Thy1, fibroblast activation protein (FAP), S-100. IHC based studies have shown differences in CAFs subpopulation between ILC and IDC. Here, we explored different CAFs subpopulations between Pleomorphic and Classical ILC using multiplex immunofluorescence (mIF). Study design: Multiplex immunofluorescence (mIF) was performed on formalin-fixed paraffin-embedded (FFPE) tissue sections [(n=6, classic ILC; n=6 pleomorphic ILC)] stained with Opal 7-color Kit using an automated system. Sections were stained consecutively with Pancytokeratin, CD45, A-SMA, FAP, S100, Thy-1. Slides were scanned using the Vectra 3.0 spectral imaging system (PerkinElmer). Five tumor ROIs were examined with Phenochart (Akoya/PerkinElmer) viewer and subsequent images were analyzed to explore spatial distances of CK+ cells to the CAFs. Data was generated using InForm and Phenoptr softwares (Akoya Labs) as a median value. Statistical analysis data correlation was performed using SPSS version 24.0 (IBM Corp) Results: Twelve invasive lobular carcinomas cases were evaluated. All cases with classical features were nuclear grade 2 and all pleomorphic cases (n=6) were nuclear grade 3. Six were Luminal B, five were Luminal A and one case was triple negative invasive lobular carcinoma. We studied nineteen different phenotypes of CAFs in the tumor, stroma, and overall tissue compartments. We found statistically significant differences (p-value&amp;lt; 0.05) between the distances of CAFs from the tumor cells in classic and pleomorphic ILC in three phenotypes. The A-SMA+, A-SMA+/S100+ phenotypes were closer to the tumor cells in classic subtype and the S100 only phenotype was closer to the tumor cells in pleomorphic carcinomas. In addition, there were two other phenotypes namely A-SMA+/Thy-1+(closer to tumor cells in classic ILC) and FAP+/S-100+ (closer to tumor cells in pleomorphic ILC), which showed a trend of significance (Table 1) Discussion: TME studies in invasive breast lobular carcinoma have been primarily based on chromogenic IHC. Multiplex immunofluorescence quantifies cell phenotype’s densities and positions in different tissue compartments (tumor vs stroma vs total tissue). Knowing the proximity of an individual TME cells to the tumor cells, aids in pinpointing possible therapeutic targets. Fibroblast dysregulation in cancers, enhances their pro-tumorigenic and anti-tumorigenic potential. Due to their heterogeneity, they can express a wide array of markers. Identifying the full possibility of CAF subsets is one of the keys to discovering actionable targets. Our results showed Alpha- SMA positive, Alpha-SMA/S-100 positive, Alpha SMA/Thy-1 positive CAFs in closer proximity to the classic ILC tumor cells as compared to pleomorphic ILC. Additionally, S-100 positive and FAP/S-100 positive CAFs showed a closer proximity to tumor cells in the pleomorphic subtype. Based on these results we hypothesize that pleomorphic ILCs are closely associated with pro-tumorigenic CAFs as compared to classic ILCs. Larger datasets are needed to confirm this. In conclusion we utilized an objective approach to quantify, phenotype and spatially correlate each cell in the tumor microenvironment. This has helped identifying CAFs subsets that differs in the spatial correlation to tumor cells in ILC subtypes, which can be potential actionable targets. Table 1 Phenotypes of Cancer associated fibroblasts and their statistical correlation between classic vs pleomorphic invasive Lobular carcinomas. Citation Format: Harsh Batra, Renganayaki K. Pandurengan, Heladio P. Ibarguen, Salome A McAllen, Qingqing Ding, Aysegul Sahin, Ignacio Wistuba, Edwin Roger Parra, Maria Gabriela Raso. Exploring spatial correlations in Breast invasive Lobular Carcinoma subtypes using a novel CAF multiplex immunofluorescence panel [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-07.

Abstract ED3-1: Updates in the pathology of PABC

Abstract Updates in the Pathology of Pregnancy Associated Breast Cancer (PABC) Pregnancy associated breast cancer is defined as a breast cancer diagnosed during gestation, lactation and within 1 to 5 years postpartum. While the development of malignancy during pregnancy is rare, the incidence is increasing; breast cancer is one of the most common cancers diagnosed during pregnancy and the postpartum period occurring in up to 1 in 3000 deliveries. Of interest, breast cancer is the leading cause of cancer death in US women age 15-29. Pregnancy has a dual effect on breast cancer development: on one hand cancer protective and on the other cancer promoting. While a number of hypotheses have been proposed over the years to explain these effects, the most likely hypothesis for the development of PABC is the involution hypothesis. This hypothesis proposes that the involution pathways activated during pregnancy and the immediate postpartum period are remodeling programs similar to wound healing and inflammation that may be associated with tumor development and progression. Although PABCs can be any subtype of breast carcinomas, they are usually invasive ductal carcinomas of high tumor grade and large tumor size with higher stage at presentation and higher rates of lymph node involvement. Most PABCs are hormone receptor negative tumors with high Ki-67 proliferation rates; most frequently, they are either triple negative or HER2-positive carcinomas. A number of studies have shown that PABCs have different genomic signatures than the non-PABC tumors with PABCs having an increased expression of immune response mediators. Better understanding of the molecular pathways of tumor initiation and progression and prompt diagnosis and state-of-art treatment protocols in PABC is expected to lead to better outcomes for these young breast cancer patients. Citation Format: Kalliopi Siziopikou. Updates in the pathology of PABC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED3-1.

Abstract P2-11-27: Peritumoral desmoplasia in breast cancer – does it matter?

Abstract Background: The peritumoral deposition of collagen is termed desmoplasia. It is characterized by the formation of new extracellular matrix, resulting from activation of tumor-associated fibroblasts. In other cancer entities (e.g. pancreatic and thyroid cancer), the presence of desmoplasia has significant prognostic impact. Furthermore, in preclinical models, targeting desmoplasia therapeutically to normalize the microenvironment has shown promising results. Yet, the role of desmoplasia in breast cancer is still unclear and data regarding this topic is rare. The aim of this study is to investigate whether desmoplasia is present in breast cancer and whether it is associated with other prognostic factors. Methods: We retrospectively analyzed 361 patients with breast cancer who had oncologic surgery at the University Hospital Leipzig, Germany between 2015 and 2018. Patients underwent operation without any preoperative therapy, after neoadjuvant chemotherapy, or after neoadjuvant endocrine treatment. One patient had had radiation in the past. Information regarding desmoplastic tumor reaction and other pathologic characteristics were retrospectively retrieved from the pathology reports. Results: Overall, data regarding desmoplasia was available for 197 patients. Median patient age was 61 years [IQR 50-73] with the most frequent tumor entity (62.9%) being invasive carcinoma of no special type (NST). 184 (93.4%) patients had either a T1 or T2 stadium. Patients had no preoperative therapy, neoadjuvant chemotherapy, or neoadjuvant endocrine treatment in 131 (66.5%), 36 (18.3%) and 29 (14.7%) cases, respectively. Desmoplasia was present in 151 cases. 46 cases showed no evidence for desmoplasia. Median age was almost similar in both groups (60.5 years vs. 61 years). Presence of desmoplasia was not associated with lymph node metastasis (pN1: 26.1% in patients with desmoplasia vs. 31.1% in patients without desmoplasia). Furthermore, there were only small differences in tumor grade between the two groups (G1: 45.7%, G2: 37.8%, G3: 15.9% [patients with desmoplasia] vs. G1: 39.1%, G2: 43.5%, G3: 17.4% [patients with no desmoplasia]. Tumor stages pT1 and pT2 were approximately equal in the two groups (pT1: 66.2% vs. 65.2%, pT2: 29.1% vs. 21.7%). There was a slight trend towards a higher (pT3) tumor stage in patients with desmoplasia (13%) compared to the patients with no desmoplasia (2.7%). Interestingly, the presence of desmoplasia was significantly associated with a higher number of Luminal A subtypes (64.2% vs. 47.8%, p-value: 0.047) and a lower number of triple negative carcinoma (10.6% vs. 17.4%. p-value: 0.22). Conclusions: In our analysis, the presence of desmoplasia is not associated with a more aggressive phenotype of breast cancer. There are hints for an association with a favorable subtype. Larger studies are necessary to validate these data and gain further information. Citation Format: Laura Weydandt, Benjamin Wolf, Lars-Christian Horn, Bahriye Aktas. Peritumoral desmoplasia in breast cancer – does it matter? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-27.

Invasive lobular triple negative carcinoma of breast: A clinico-pathological study done in south eastern part of India

Background: Triple Negative Breast Carcinomas (TNBC) are breast carcinomas which are negative for Estrogen receptor (ER) Progesterone receptor (PR) and no overexpression of Human Epidermal Growth Factor receptor-2 (HER-2). The five-year survival rate for breast carcinomas in general is good but the same is bad for TNBC. TNBC has got worse prognosis compared to hormone positive breast carcinomas. Aim: The aim of present study is to compare invasive lobular TNBC with invasive ductal TNBC with morphologic, immunohistochemical and prognostic parameters. Materials and Methods: One-year study was done at Tertiary Care Centre. Patients of all ages were included. Most of them were in 4th and 5th decade. Mammography, FNAC and Biopsy was done. Formalin-fixed mastectomy specimens received at MGM hospital are screened, diagnosed histopathologically for carcinoma of breast over a period of one year. Immunohistochemistry (IHC) was performed to diagnose TNBC. Results: Total no of cases – 72. No of Cases with positive ER, PR and or Her 2/neu are – 61. No of Cases with ER, PR and Her 2/neu negative (Triple negative) – 11 Percentage of Triple negative cases – 15 %. Most of the TNBCs show high grade and high mitotic count 74% and 82% respectively. Other hand, some cases 60% showed only ER and PR positivity without Her-2 and 25% showed only Her-2 positivity without ER and PR. Invasive lobular TNBC subtype is reported in 18%. Conclusion: Overall TNBCs are high grade aggressive tumors and are more common in younger age groups. Whereas TNBCs associated with invasive lobular carcinoma are more common in 5th decade and were more aggressive compared to other subtypes.