bluuebunny/crossref_metadata_2025 huggingface dataset:
The Vedotin Antibody–Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles
Authors: Neff-LaFord Haley D. , Carratt Sarah A. , Carosino Christopher , Everds Nancy , Cardinal Kristen A. , Duniho Steven , Schutten Melissa M. , Frantz Christopher , Zuch de Zafra Christina , Harstad Eric B.
Published: May 2024

Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody–drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.
Abstract ED01-01: Optimizing endocrine therapy in premenopausal women
Authors: Stearns V.
Published: May 2024

Premenopausal women with early-stage hormone receptor (HR)-positive breast cancer are candidates for adjuvant endocrine therapy and have several treatment options. The clinical team should assess an individual woman’s risk of recurrence, estimate benefits from specific endocrine manipulations, and consider co-morbidities, adverse event profile and host factors. Risk stratification strategies including clinic-pathologic features, genomic assays and composite scores can guide recommendations regarding type and duration of endocrine therapy, in particular in node-negative disease. Adjuvant tamoxifen for 5 to 10 years significantly reduces breast cancer recurrence and death. Premenopausal women who are at high risk of recurrence benefit from ovarian function suppression (OFS) with tamoxifen or an aromatase inhibitor for 5 years. Those include women with high-risk clinico-pathological features and younger age, and for whom chemotherapy is commonly recommended. There are currently no available data regarding the use of extended OFS beyond 5 years. Newer data support the addition of CDK 4/6 inhibitors to endocrine therapy in women with high-risk disease. Endocrine therpay is associated with frequent bothersome and few significant side effects that can negatively impact quality of life and adherence to treatment. Clinicians must carefully weigh the benefits associated with specific endocrine therapies, and possible short- and long-term side effects to individualize therapy, and to consider interventions to enhance adherence.

Citation Format: V. Stearns. Optimizing endocrine therapy in premenopausal women [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 ED01-01.
Abstract ED07-03: Novel Systemic Therapy Strategies for HER2+ Brain Metastases
Authors: Sammons S.
Published: May 2024

More than 1/3 of patients with HER2+ metastatic breast cancer will develop brain metastases. Local therapies such as resection or radiation therapy continue to play a pivotal role in brain metastases treatment. However, receipt of HER2-directed systemic therapies lead to significant survival advances for both stable and active brain metastases and are integral to optimal outcomes. We will review clinical goals for stable and active brain metastases. In the last few years, novel early line systemic therapy regimens have improved outcomes for HER2+ brain metastases which will be reviewed. We will review evolving evidence that Antibody Drug Conjugates targeting HER2 have robust intracranial activity. We will review exciting HER2 directed tyrosine kinase inhibitors and combinations.

Citation Format: S. Sammons. Novel Systemic Therapy Strategies for HER2+ Brain Metastases [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 ED07-03.
Abstract PO1-04-06: Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with metastatic breast cancer
Authors: Singh Indrajeet , Sathe Abhishek , Diderichsen Paul , Witjes Han , Van Schanke Arne , Maringwa John , Verret Wendy , Girish Sandhya , Othman Ahmed
Published: May 2024

Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate that is composed of an anti Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolysable CL2A linker. SG (10 mg/kg on D1 and D8 of every 21D cycle) is approved for patients (pts) with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in the metastatic setting). The relationship between exposure of SG, free SN-38, and total antibody (tAB) following SG administration and its efficacy and safety were evaluated in pts with HR+/HER2‒ metastatic breast cancer (mBC) and all pts with mBC (mTNBC or HR+/HER2‒ mBC), respectively. Methods: Available exposure and efficacy outcomes from HR+/HER2‒ mBC pts from phase 3 study TROPiCS-02 (n=260) and safety outcomes from mBC pts in phase 1/2 study IMMU-132-01, phase 3 study ASCENT and TROPiCS-02 (total n=569) were analyzed. Exposure-response (ER) models were developed to characterize the relationship between exposure and efficacy (complete response [CR], overall response rate [ORR], clinical benefit rate [CBR], overall survival [OS] and progression-free survival [PFS]) and safety (adverse events [AEs] of vomiting, diarrhea, hypersensitivity reactions, nausea, neutropenia, febrile neutropenia, time to first dose reduction and first dose delay) endpoints. Exposure metrics of SG, free SN-38, and tAB were evaluated as predictors and effect of clinically relevant covariates was characterized within the modeling framework. Results: Average SG-related serum exposures over the duration of treatment (until the event) were associated with significantly increased efficacy (probability of CR, ORR, CBR and longer OS and PFS) and safety events (probability of any grade AE). Neutropenia was the only AE where the increase in exposure was significantly associated with the increased probability of Grade ≥3 and Grade 4 events. Baseline Trop-2 expression level was not correlated with assessed efficacy and safety endpoints. Conclusions: Within the exposure range achieved with the 10 mg/kg regimen, higher exposure values were associated with a higher probability of achieving better efficacy. The 10 mg/kg SG dose achieved an acceptable balance between efficacy and safety which supports the appropriateness of this regimen in pts with HR+/HER2‒ mBC.

Citation Format: Indrajeet Singh, Abhishek Sathe, Paul Diderichsen, Han Witjes, Arne Van Schanke, John Maringwa, Wendy Verret, Sandhya Girish, Ahmed Othman. Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with metastatic 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 PO1-04-06.
Abstract PO1-14-03: Discovery of proliferation essential gene signature and ACTL6A as potential biomarker for predicting prognosis and neoadjuvant therapy response in triple-positive breast cancer
Authors: Li Xiaofen , Fu Wenfen , Luo Shiping , Zhang Jie , Wang Qingshui , Song Chuangui
Published: May 2024

Background: Based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), a special subtype of breast cancer which expresses all three receptors can be distinguished, namely triple-positive breast cancer (TPBC). TPBC patients has a higher risk of recurrence and lower survival rate compared to other luminal breast cancers. However, there are few studies on predicting molecules of prognosis and treatment response for TPBC. Methods: Proliferation essential genes (PEGs) were identified using CRISPR-Cas9 dataset of DepMap. The expression profiles and clinical data of TPBC were obtained from the TCGA database, GEO datasets and our center cohort. To develop a TPBC-PEG prognostic signature, cox regression and Lasso (Least absolute shrinkage and selection operator) regression analysis were applied. Functional analysis was performed using Gene Set Enrichment analysis. Finally, the relationship between candidate genes and neoadjuvant therapy (NAT) sensitivity was explored using real-time qPCR (RT-qPCR) and immunohistochemistry (IHC) based on clinical samples. Results: Among 900 TPBC-PEGs, 437 genes showed significant differential expression between TPBC and normal tissues. Subsequently, we identified 3 prognostic PEGs (ACTL6A, CCT2, TARS) and used them to construct a PEG signature. Patients with high PEG signature scores exhibited worse overall survival and lower sensitivity to NAT compared to those with low PEG signature scores. RT-qPCR indicated that in patients who lacked sensitivity to NAT, ACTL6A and CCT2 were significantly upregulated. The IHC results showed that ACTL6A protein was highly expressed in the NAT-insensitive group and non-pathological complete response patients. Conclusion: In this study, we developed an efficient PEG prognostic model that can predict the outcome for TPBC. Furthermore, we found that the expression of ACTL6A is associated with neoadjuvant therapy sensitivity in TPBC patients and can serve as an important factor in predicting patient prognosis and drug sensitivity.

Figure 3. Construction and validation of a PEG signature for TPBC patients.

Figure 6. The predictive value of ACTL6A on NAT efficacy and its correlation with clinical characteristics.

Citation Format: Xiaofen Li, Wenfen Fu, Shiping Luo, Jie Zhang, Qingshui Wang, Chuangui Song. Discovery of proliferation essential gene signature and ACTL6A as potential biomarker for predicting prognosis and neoadjuvant therapy response in triple-positive 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 PO1-14-03.
Abstract PO1-25-07: Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment
Authors: Ritter Andreas , Solbach Christine , Yuan Juping
Published: May 2024

Objective:

Breast cancer is the most frequently diagnosed cancer and a common cause of cancer related death in women. The breast cancer microenvironment (TME) is mainly composed of adipose tissue, consisting of adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells. Interestingly, it is well recognized that obesity, as indicated by increased body mass index (BMI≥30), is associated with an enhanced risk of more aggressive breast cancer (BC) as well as reduced patient survival. Therefore, we asked how BC affects the biological functionality of bASC, how obesity fuels this process, and on the other hand how these cells influence BC cells.

Methods:

Multiple molecular biological approaches as transcriptomic profiling and diverse functional assays were conducted to characterize at least 5 lean and obese patients derived bASCs samples near the TME (lean/obese-aT) or distant (lean/obese-dT). Afterwards, these cells were used to investigate the interaction with BC cells in 2-dimensional and 3-dimensional cell culture experiments. Moreover, immunohistological analyses were conducted in 16 lean and 16 obese breast cancer patients (grade 3-4).

Results:

The TME shifts bASCs towards cancer supporting phenotypes into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype with a significant deregulated gene expression, cytokine/chemokine secretion, and reduced differentiation capacity. In corroberation, these BMI dependent de-differentiation processes could be confirmed in breast cancer tissue. Moreover, the cell-cell interaction of BC cells with aT-bASCs increased their proliferation, motility, and chemoresistance.

Conclusions:

The study found multiple pathways deregulated in bASCs associated with tumor promoting effects. Additionally, it revealed the role of aT-bASCs in promoting breast cancer progression on a functional and molecular level.

Citation Format: Andreas Ritter, Christine Solbach, Juping Yuan. Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment [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 PO1-25-07.
Abstract PO2-08-04: Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics
Authors: Karaayvaz Mihriban , Caputo Anthony , Vipparthi Kavya , Bazeley Peter , Downs-Kelly Erinn , McIntire Patrick , Ni Ying , Hu Bo , Keri Ruth
Published: May 2024

Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for BRCA1/2 mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells differs from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.

Citation Format: Mihriban Karaayvaz, Anthony Caputo, Kavya Vipparthi, Peter Bazeley, Erinn Downs-Kelly, Patrick McIntire, Ying Ni, Bo Hu, Ruth Keri. Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics [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 PO2-08-04.
Abstract PO2-08-06: Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment
Authors: Shiba Satomi , Harao Michiko , Ogihara Kasumi , Fukuda Takayo , Sakuragi Masako , Joji Kitayama , Sata Naohiro
Published: May 2024

Metformin, an anti-diabetic drug, is known to have anti-tumor effects. We examined the outcome of 177 patients with type 2 diabetes mellitus (T2DM) who received surgery for breast cancer. Among them, 49 patients were treated with drugs including metformin. In those patients, recurrence in distant organs was less frequent and postoperative disease-free survival (DFS) tended to be better than those without metformin intake. In patients who received preoperative systemic therapy (PST), rate of pathological complete response (pCR) was significantly more frequent in patients with metformin treatment (p < 0.05). Multiplex immunohistochemical staining of resected tumors revealed that the density of tumor associated macrophages (TAM), especially of CD68(+)CD163(+) M2-type TAM, was significantly lower in tumors with metformin treatment. In contrast, the rate of CD8(+) phenotype in CD3(+) tumor infiltrating lymphocytes (TILs) was significantly higher in metformin group. The results suggest that metformin can change the immune microenvironment from pro-tumorigenic to anti-tumorigenic status, which leads to the favorable outcome of the patients with breast cancer and T2DM.

Citation Format: Satomi Shiba, Michiko Harao, Kasumi Ogihara, Takayo Fukuda, Masako Sakuragi, Kitayama Joji, Naohiro Sata. Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment [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 PO2-08-06.
Abstract PO2-14-11: Proteogenomic approaches for the identification of NF1/neurofibromin-depleted estrogen receptor positive breast cancers for targeted treatment
Authors: Kim Beom-Jun , Zheng Ze-Yi , Lei Jonathan , Holt Matthew , Chen Anran , Peng Jianheng , Fandino Diana , Singh Purba , Kennedy Hilda , Dou Yongchao , Chica-Parrado M Rosario , Bikorimana Emmanuel , Ye Dan , Wang Yunguan , Hanker Ariella , Mohamed Nada , Hilsenbeck Susan , Lim Bora , Asirvatham Jaya Ruth , Sreekumar Arun , Zhang Bing , Miles George , Anurag Meenakshi , Ellis Matthew , Chang Eric
Published: May 2024

NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader (SERD), together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ PDX models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pull-down. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An immunohistochemistry (IHC) assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis.

Citation Format: Beom-Jun Kim, Ze-Yi Zheng, Jonathan Lei, Matthew Holt, Anran Chen, Jianheng Peng, Diana Fandino, Purba Singh, Hilda Kennedy, Yongchao Dou, M Rosario Chica-Parrado, Emmanuel Bikorimana, Dan Ye, Yunguan Wang, Ariella Hanker, Nada Mohamed, Susan Hilsenbeck, Bora Lim, Jaya Ruth Asirvatham, Arun Sreekumar, Bing Zhang, George Miles, Meenakshi Anurag, Matthew Ellis, Eric Chang. Proteogenomic approaches for the identification of NF1/neurofibromin-depleted estrogen receptor positive breast cancers for targeted treatment [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 PO2-14-11.
Abstract PO2-25-02: The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer
Authors: Wang Hai
Published: May 2024

Immunotherapy has achieved limited success in patients with triple-negative breast cancer (TNBC), an aggressive disease with a poor prognosis. Commensal microbiota have been proven to colonize the mammary gland, but whether and how they modulate the tumor microenvironment remains elusive. We performed a multiomics analysis of a cohort of patients with TNBC (n = 360) and found genera under Clostridiales, and

the related metabolite trimethylamine N-oxide (TMAO) was more abundant in tumors with an activated immune microenvironment. Patients with higher plasma TMAO achieved better responses to immunotherapy. Mechanistically, TMAO induced pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8+ T cell-mediated antitumor immunity in TNBC in vivo. Collectively, our findings offer new insights into microbiota-metabolite-immune crosstalk and indicate that microbial metabolites, such as TMAO or its precursor choline, may represent a novel therapeutic strategy to promote the efficacy of immunotherapy in TNBC.

Citation Format: Hai Wang. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in 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 PO2-25-02.
Abstract PO2-26-06: Prognostic factors pregnancy associated breast cancer: one year versus two years
Authors: Izquierdo Maxim , Baulies Sonia , Ara Carmen , Garcia Maria , Fargas Fransec , Fabregas Rafael , Tresserra Fransec , S Pere Barri
Published: May 2024

Aims: The trend of delayed delivery, the number of women with breast cancer during a pregnancy or in the years after pregnancy is expected to increase Pregnancy breast cancer confers a worse prognostic. Study if the interval pregnancy breast cancer more one year to two years influences the prognostic factors like pregnancy breast cancer one year after Methods: Study 1186 patients with breast cancer and prognostic factors. Analyze delivery before breast cancer, and the interval of last childbirth, one year, more one year to two years and more two years, with prognostic factors (nodes, estrogen receptor, progesterone receptor, HER2 receptor and Ki 67) Results: Breast cancer pregnancy one year after were in 37 patients, more one year to two years in 25 patients and more two years in 491 patients. Positive nodes one year after were in 21 patients, more one year to two year were in seven patients (p < 0'05), and more two years in 155 patients (p=ns). There are not differences (p=ns) in estrogen receptor, progesterone receptor and Ki67, one year versus more one year to two years and more to two years. HER2 and histologic grade there are not differences (p=ns) in one year after versus more one year to two years, but there are differences (p < 0’05) versus more two years Conclusion: Interval last childbirth breast cancer more than one year to two years influences prognostic factors for later breast cancer, and not have differences with prognostic factors than pregnancy one year after

Citation Format: Maxim Izquierdo, Sonia Baulies, Carmen Ara, Maria Garcia, Fransec Fargas, Rafael Fabregas, Fransec Tresserra, Pere Barri S. Prognostic factors pregnancy associated breast cancer: one year versus two years [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 PO2-26-06.
Abstract PO3-03-09: Clinical Significance of Grade in Triple Negative Breast Cancer
Authors: Malik Mah-noor , Ramanan Neya , Upneja Sarang , Brackstone Muriel , Porter Lisa , Fifield Bre-Anne , Hamm Caroline
Published: May 2024

Triple negative breast cancer (TNBC) is a heterogeneous cancer type that lacks receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor receptor-2 proteins (HER-2). An important prognostic factor for breast cancer patients is the tumour grade, which is the degree of cell proliferation or differentiation of the tumour cells from normal cells. In our initial study involving 305 TNBC patients from 2004-2017 at Windsor Regional Hospital Cancer Centre, we found a statistically significant difference between grade 2 and grade 3 patients, with grade 2 predicting significantly inferior progression-free and overall survival. In our initial study, the overall survival rates for grade 1, 2, and 3 tumours were 90.12%, 64.4%, and 77.2% respectively (p = 0.019) with relapse rates of 70%, 55.6%, and 75.6% respectively (p = 0.04). Our current study is an attempt to validate these initial findings by expanding our data set to include data from the London Health Sciences Centre. A literature review on TNBC and grade was conducted, followed by a retrospective chart review for 305 TNBC patients from the Windsor Regional Hospital and 515 TNBC patients from the London Health Sciences Centre. The parameters for data collection included patient demographics, tumour demographics, therapies, and patient outcomes. We calculated all patient stages using both American Joint Committee on Cancer 7th edition (AJCC7) and the updated AJCC8 staging systems. Initial review of the data supports our earlier findings with a relapse rate of 12.5% in patients with grade 3 tumours and 17% in patients with grade 1 and grade 2 tumours. The completed data set will be analyzed and presented at the conference. Validating our previous findings of significantly inferior patient outcomes for grade 2 compared to grade 3 patients may alter the staging system used for TNBC patients.

Citation Format: Mah-noor Malik, Neya Ramanan, Sarang Upneja, Muriel Brackstone, Lisa Porter, Bre-Anne Fifield, Caroline Hamm. Clinical Significance of Grade in 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 PO3-03-09.
Abstract PO3-23-04: Patient-reported outcomes and complication profiles of implant-based breast reconstruction in patients with postmastectomy radiation therapy
Authors: Liu Jian , Chen Cong , Chen Honggang , Xiang Aizhai , Zheng Ruzhen , Hu Shufang , Guo Jufeng , Qu Li , Zhou Jun , Wu Jiong
Published: May 2024

Objective: This study aims to investigate the patient-reported outcomes (PROs) and complications of distinct implant-based breast reconstruction (IBBR) modality for patients with postmastectomy radiation therapy (PMRT).

Methods: A retrospective review was conducted on breast cancer patients with stage II-III disease who performed IBBR following with PMRT between September 2016 and April 2022. The patients were categorized into two matched groups: (1) patients receiving prepectoral breast reconstruction (PBR) or subpectoral breast reconstruction (SBR) followed by PMRT; (2) patients undergoing PMRT with the tissue expander (PMRT-TE) or permanent implant (PMRT-PI) groups. PROs were measured with BREAST-Q questionnaire. Early and late complications were recorded and analysed.

Results: A total of 55 eligible patients were recruited. For PROs, patients underwent PBR reported significantly higher Satisfaction with Breasts scores (P = 0.003) compared with SBR group, and PMRT-TE group presented higher Satisfaction with Breasts (P = 0.001) but lower Physical Well-being (P = 0.029) scores compared with PMRT-PI group. Moreover, Patients in SBR cohort had a higher risk of capsular contracture (Baker grade III or IV) (20.5% vs 6.3%) and implant dislocation (48.7% vs 12.5%) than patients in PBR cohort. Patients in PMRT-PI group had a slightly higher rate of capsular contracture (Baker grade III or IV) than PMRT-TE group (20.8% vs 12.9%).

Conclusions: PBR was associated with lower rates of late complications, especially for implant dislocation, and higher Satisfaction with Breasts scores compared to SBR. In addition, compared to PMRT-TE with PMRT-PI, patients in PMRT-TE cohort reported superior patient-reported outcomes of Satisfaction with Breasts.

Table 1. Patient and Tumor Characteristics of 55 Patients Stratified with Prepectoral/Subpectoral and PMRT-TE/PMRT-PI Reconstructive Procedure. XX- XX

Table 2. Patient-Reported BREAST-Q Scores XX- XX

Table 3. Association of Reconstruction Techniques with Late Complications. XX- XX

Citation Format: Jian Liu, Cong Chen, Honggang Chen, Aizhai Xiang, Ruzhen Zheng, Shufang Hu, Jufeng Guo, Li Qu, Jun Zhou, Jiong Wu. Patient-reported outcomes and complication profiles of implant-based breast reconstruction in patients with postmastectomy radiation therapy [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 PO3-23-04.
Abstract PO3-23-10: Continued treatment with CDK4/6 inhibitors slow tumor progression by extending G1-phase duration in drug resistant populations
Authors: Armand Jessica , Kim Sungsoo , Yang Hee Won
Published: May 2024

CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis of patients with metastatic hormone receptor-positive breast cancer. However, the development of drug resistance leads to the discontinuation of CDK4/6i treatment. The potential benefits of maintaining CDK4/6i treatment in the context of resistance and their underlying molecular mechanisms remain elusive. Here we show that despite tumor progression, continued treatment with CDK4/6i notably extends the G1 phase in drug-resistant cells, thereby slowing their growth. Our single-cell data reveal that the duration of the G1 phase in these resistant cells is approximately tripled under continuous CDK4/6i treatment compared to conditions with CDK4/6i withdrawal, while the durations of the S and G2 phases remain comparable. The maintenance of CDK4/6i induces an alternative inactivation of the retinoblastoma (Rb) protein in drug-resistant cells through its post-translational degradation. However, this alternative form of Rb inactivation is ineffective and thus induces slow activation kinetics of E2F transcription factors, significantly delaying G1 progression. The beneficial effect of maintaining CDK4/6i treatment was further validated in breast cancer xenograft models. Furthermore, our findings suggest that given the spectrum of various CDK4/6i, switching between different CDK4/6i types after the emergence of drug resistance may further delay tumor progression. This study provides new mechanistic insights into the maintenance of CDK4/6i treatment despite the development of drug resistance.

Citation Format: Jessica Armand, Sungsoo Kim, Hee Won Yang. Continued treatment with CDK4/6 inhibitors slow tumor progression by extending G1-phase duration in drug resistant populations [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 PO3-23-10.
Abstract PO3-24-03: Cisplatin synergizes immune checkpoint blocking through RNFT1 mediated PD-L1 recycling in Triple Negative Breast Cancer
Authors: Chu Jiahui , Zhang Yifan , Hua Yijia , Gong Jue , Mei Jie , Fu Ziyi , Yi Yongmei
Published: May 2024

Since chemotherapy showed synergies with PD-1/PD-L1 blockage therapy in solid tumors, the efficacy in triple negative breast cancer (TNBC) varies greatly and only a subset of patients achieves durable responses. To increase their clinical efficacy, it is important to explore the underlying mechanisms of immune checkpoint ligand PD-L1. Here, we found cisplatin influenced the controlled intracellular transport of PDL1 by inducing the RNFT1-mediated endoplasmic reticulum autophagy. Overexpression of RNFT1 increases the endocytosis-recycling rate of the plasm membrane PD-L1, which is regulated by K63-polyubiquitination and endoplasmic reticulum autophagy degradation of PD-L1, thereby having negative impact on antitumor immunotherapy, such as reduced effective drug concentration and avoiding immune surveillance. Genetically or pharmacologically modulating RNFT1-induced K63 polyubiquitination blocks endocytosis of PD-L1, consequently enhances the antitumor response to PD-L1 blockade. Thus, our results suggest that cisplatin treatment is involved in RNFT1-induced K63 polyubiquitination of PD-L1 endocytosis-recycling pathway that governs immune response, and blocking RNFT1 might enhance the efficacy of PD-1/PD-L1 blockade. These studies have high application and translational potential in triple-negative breast cancer.

Citation Format: Jiahui Chu, Yifan Zhang, Yijia Hua, Jue Gong, Jie Mei, Ziyi Fu, Yongmei Yi. Cisplatin synergizes immune checkpoint blocking through RNFT1 mediated PD-L1 recycling in 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 PO3-24-03.
Abstract PO4-09-03: Environmental Metal Exposures and Breast Cancer Risk: A Prospective Study of Nationally Representative Canadian Data
Authors: Pullella Katherine , Lubinski Jan , Hanley Anthony , Harris Shelley , Narod Steven , Kotsopoulos Joanne
Published: May 2024

Introduction: The impact of metal exposure on breast cancer risk remains unclear. Studies have explored metals independently with limited investigation into chronic exposures and mixture analyses. This project describes exposure to eight heavy and essential metals and evaluates the association between metals and breast cancer risk, independently and in a mixture, among Canadian women.

Methods: Demographic information and concentrations of urinary or blood metal biomarkers from 2007-2017 of the Canadian Health Measures Survey (CHMS) were analyzed. Incident breast cancers were ascertained through linkage to the Canadian Cancer Registry. Metal exposure was described using weighted percentiles and categorized by tertiles. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for metal exposure and breast cancer risk. Quantile g-computation was used to estimate the joint association between metal exposure and breast cancer risk.

Results: This analysis included 5,100 women (mean age 44.6 years) with an average follow-up of 6.6 years. Higher urinary arsenic (> 13.0 µg/L) and cadmium (> 10.0 µg/L) had a significant increased risk of breast cancer (HR Arsenic T3 vs. T1 = 2.05; 95%CI 1.05-3.94; HR Cadmium T3 vs. T1 = 1.71; 95%CI 1.01 – 5.87). Analyses into the joint association between the metal exposure mixture and breast cancer risk are ongoing, and matrix results will be presented.

Conclusion: This represents the first evaluation of metal exposure and breast cancer risk in a nationally representative cohort. Our findings suggest that arsenic and cadmium, even at low levels, may be associated with an increased risk of breast cancer. These findings can inform population-level interventions to reduce the burden of cancer in Canada.

Citation Format: Katherine Pullella, Jan Lubinski, Anthony Hanley, Shelley Harris, Steven Narod, Joanne Kotsopoulos. Environmental Metal Exposures and Breast Cancer Risk: A Prospective Study of Nationally Representative Canadian Data [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 PO4-09-03.
Abstract PO4-20-02: A prospective, randomized, controlled clinical trial comparing different PEG-rhG-CSF administration times to treat chemotherapy-induced neutropenia and febrile neutropenia in early breast cancer
Authors: Zha Xiaoming , Wang Jue , Xu Yinggang , He Jinzhi , Wang Ye , Zhang Weiwei , Wan Xinyu , Shi Wenjie
Published: May 2024

Background: Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) injection time is still referred as recombinant human granulocyte CSF (rhG-CSF) as a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. The trial examined whether PEG-rhG-CSF injection on day 7 following chemotherapy was superior to injection on day 3.

Patients and methods: Patients with early breast cancer were randomly assigned to receive a preventive injection on days 7 or 3 following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n=80) received it on day 3. The occurrence of grades 3–4 neutropenia and FN was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction.

Results: Compared with the control group, the white blood count (WBC) or absolute neutrophil count (ANC) in the experimental group was higher on days 9 and 13 (P < 0.05) after chemotherapy, and the incidence of grade 3–4 neutropenia was lower (P = 0.038). The experimental group met the standard for lowering the PEG-rhG-CSF dose were more than that in the control group (69.74% vs. 35.06%, P < 0.001). Patients receiving a lower PEG-rhG-CSF dose had higher WBC count and ANC after chemotherapy, but were more likely to suffer from mild arthralgia. (P < 0.05).

Conclusion: In comparison with PEG-rhG-CSF injection on day 3 after chemotherapy, the incidence of grade 3–4 myelosuppression is lower, and the safety is more manageable after the injection on day 7. Thus, more patients will receive dose reduction and lower patient medical costs.

Citation Format: Xiaoming Zha, Jue Wang, Yinggang Xu, Jinzhi He, Ye Wang, Weiwei Zhang, Xinyu Wan, Wenjie Shi. A prospective, randomized, controlled clinical trial comparing different PEG-rhG-CSF administration times to treat chemotherapy-induced neutropenia and febrile neutropenia in early 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 PO4-20-02.
Abstract PO4-22-08: Ten-Year Oncologic Outcomes in T1-3N1 Breast Cancer After Targeted Axillary Sampling: A Retrospective Study
Authors: Kang Byeongju , Lee Jeeyeon , Chae Yee Soo , PARK Ho Yong , Jung Jin Hyang
Published: May 2024

Background

Targeted axillary sampling (TAS) is a new surgical concept for the assessment of axillary lymph node status in breast cancer that is hypothesized to be more effective at minimizing postoperative morbidities than axillary lymph node dissection (ALND), provided the metastatic axillary lymph node can be accurately detected without missing data; however, the oncologic outcomes over long-term follow-up have not been sufficiently investigated. This was a retrospective analysis to evaluate the 10-year oncologic outcomes in T1-3N1 breast cancer after TAS.

Methods

Clinically, we defined TAS as removal of a bunch of ALNs located around SLNs and targeted LNs, but without full exposure of the axillary vein, long thoracic nerve and thoracodorsal nerve.

Between 2008 and 2013, 230 female patients with cT1-3N1 breast cancer underwent breast and axillary surgery (ALND, n = 171; TAS, n = 59) at our institute. After TAS was applied, additional axillary radiotherapy was performed. Various postoperative complications, including postoperative seroma, lymphedema, and 10-year oncological outcomes, were evaluated and compared between the ALND and TAS groups.

Results

Although overall survival during the 10-year follow-up period was better in the TAS group, there was no statistically significant difference in oncologic outcomes, including locoregional recurrence, distant metastasis, and overall survival (p = 0.395, 0.818, and 0.555, respectively). Furthermore, the incidence of lymphedema on the ipsilateral arm was significantly higher in the ALND group (p < 0.001).

Conclusions

The 10-year oncological outcomes of TAS were not inferior to those of conventional ALND in T1-3N1 breast cancers; however, the incidence of lymphedema was significantly higher in the ALND group.

Citation Format: Byeongju Kang, Jeeyeon Lee, Yee Soo Chae, Ho Yong PARK, Jin Hyang Jung. Ten-Year Oncologic Outcomes in T1-3N1 Breast Cancer After Targeted Axillary Sampling: A Retrospective 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 PO4-22-08.
Abstract PO5-04-10: Clinical and prognostic value of MLN51 (Metastatic lymph node gene 51)/CASC3 (Cancer susceptibility candidate gene 3) in clinical breast cancer, connection with nodal and hormonal receptor status
Authors: Cong Binbin , Martin Tracey , Cao Xiaoshan , Mansel Robert E , Davies Eleri , Jiang Wen
Published: May 2024

Introduction: Metastatic Lymph Node Gene 51 Protein (MLN51) also known as Cancer Susceptibility Candidate Gene 3 Protein (CASC3) or Barentsz (BTZ) is a molecule that was first identified in malignant breast tumours. The CASC3 gene encodes the protein that binds to mRNA and is a key component of the exon junction complex (EJC), playing an important role in the metabolism of mRNA and in cellular recovery after stress responses. It is not clear, however, if MLN51 has a clinical value in assessing the disease progression of breast cancer.

Methods: We analysed the transcription expression levels of MLN51 in a cohort of human breast cancer tissues and correlated the expression pattern with clinical outcome, pathological type and hormonal receptor status.

Results: High levels of MLN51 was found to be a favourable prognostic indicator for overall survival (p=0.008, Hazard Ratio [HR=0.262]), the prognostic value being independent of other clinical and pathological factors. Likewise, high levels of MLN51 were also a significant and independent predictive factor for disease free survival (DFS) (p=0.003, HR=0.262). It was found that the favourable prediction in both OS and DFS was associated with node positive tumours, with significance with OS (p=0.004), compared in node negative tumours (p=0.143) and to DFS (p=0.001 in node positive compared with p=0.079 in node negative tumours). Levels of MLN51 had a significant correlation with EGFR in both normal and tumour mammary tissues but correlated with Her-2 and Her-3 in tumour tissues only. The prognostic power of MLN51 for DFS was significant in both Her-2 positive and Her-2 negative (p=0.003 and p=0.012) tumours and in ER negative tumours (p=0.003). The prediction for OS by MLN51 was particularly strong for Her-2 positive and ER positive (p=0.007 for both) tumours.

Conclusions: MLN51 (CASC3) is a favourable prognostic factor in patients with breast cancer. This is clearly linked to the nodal status and hormone receptor status, particularly ER and HER-2.

Citation Format: Binbin Cong, Tracey Martin, Xiaoshan Cao, Robert E Mansel, Eleri Davies, Wen Jiang. Clinical and prognostic value of MLN51 (Metastatic lymph node gene 51)/CASC3 (Cancer susceptibility candidate gene 3) in clinical breast cancer, connection with nodal and hormonal receptor status [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 PO5-04-10.
Abstract PO5-08-04: Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center
Authors: Karki Ujjwal , Rangarajan Tara , Zakalik Dana
Published: May 2024

Background:

Pathogenic variants (PVs) in ATM are associated with an increased risk of breast, pancreas, and other cancers. The clinical and pathological characteristics of ATM-associated breast cancers have not been well defined.

Methods:

Patients who underwent multigene panel testing between December 2012 and May 2023 and were identified to harbor ATM PVs were included in the study. We analyzed demographics, germline findings, histopathology, genomic recurrence score, and management of ATM PV carriers with breast cancer.

Results:

A total of 222 individuals were identified to have PVs in ATM, of whom 184 (83%) were female. The majority were Caucasian (n = 179, 81%) and of those, 22 (12%) had Ashkenazi Jewish ancestry. The median age at genetic testing was 52y, with a range of 20-90y. A total of 111 patients (50%) had a personal cancer diagnosis, the most common of which was breast cancer (n = 70; 63%). The median age at breast cancer diagnosis was 53y, with a range of 25-84y. The most common histopathology was invasive ductal carcinoma (74%), followed by DCIS (21%), and invasive lobular carcinoma (5%). The majority of patients had breast tumors with stage 2 or 3 (78%), grade 2 or 3 (92%), ER and/or PR positive (92%) and HER2 negative (70%). One patient had triple-negative breast cancer. Forty-four percent of breast cancers were less than two centimeters, 23% were lymph node-positive, and 29% had lymphovascular invasion. Thirty-eight percent of patients underwent bilateral mastectomy, 54% received radiation therapy, 40% received adjuvant chemotherapy, 24% received neoadjuvant chemotherapy, and 70% received hormonal therapy. Of the 15 breast cancers with known 21-gene recurrence scores, 47% were intermediate (11-26), 33% were high (>=26) and 20% were low (< =10). Other notable cancers observed were pancreas (n = 9), colorectal (n = 6), prostate (n = 5), uterine (n = 4), melanoma (n = 4), and thyroid (n = 4).

Conclusion:

Our study outlines the clinical and pathological characteristics of ATM-associated breast cancer in a large academic center. The majority of breast cancers were invasive ductal type, early stage, intermediate or high grade, and hormone receptor-positive with an intermediate or high recurrence score. Despite the early stage, a significant proportion of patients underwent bilateral mastectomy. Further studies are needed to better elucidate the unique characteristics of breast cancer in ATM PV carriers in order to provide tailored management guidelines for this population.

Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center [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 PO5-08-04.