bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-05-57: Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours
Authors: Badwe Rajendra , Joshi Shalaka , Hawaldar Rohini , Chaubal Rohan , Bhattacharjee Atanu , Vanmali Vaibhav , Nair Nita S. , Gupta Sudeep
Published: March 2023

Background-

Dissemination of cancer cells and their colonization at distant sites (metastases) is the primary cause of death in patients with solid tumors. Despite of popular theories of cancer metastases, there are several lacunae in our understanding of extent of Metastatic Disease at Presentation (MDP). The aim of this study was to evaluate if organ sites could be grouped together based on the available knowledge extent of lympho-vascular communication (LVC) and probable respiratory pressure changes they undergo and whether this correlated with incidence of MDP.

Methods-

We analyzed a prospectively maintained database of patients with solid tumors presenting between January and December 2017 at our tertiary care cancer center. The tumors were hypothetically divided into four regions (R) depending on extent of LVC and respiratory pressure changes. All patients had clinico-radiological staging after pathological confirmation of cancer. The hypothetical region grouping R1-R4 was independently evaluated by unsupervised k-means clustering. The incidence of MDP was compared in subgroups defined by primary tumor stage, anatomical region, histology, gender, and age using logistic regression.

Results-

Of 17,467 patients included with median age 54 years, 6714 (38.4%) had MDP. The incidence of M1 disease in R1 vs R2 vs R3 vs R4 regions, older (>50 years) vs younger

Conclusion-

Primary anatomical regions defined by LVC and respiratory pressure changes; primary tumor histology (type and grade) and male gender are significant determinants of MDP in solid tumors.

Region grouping of solid organs based on extent of lymphaticovenous communications and rhythmic respiratory pressure changes and % MDP

Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Rohan Chaubal, Atanu Bhattacharjee, Vaibhav Vanmali, Nita S. Nair, Sudeep Gupta. Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours [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 P3-05-57.
Abstract P3-07-20: Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial
Authors: Reid Tony , Kummel Andrew , Caroen Scott , Shah Jaimin , Oronsky Bryan , Larson Christopher
Published: March 2023

Adenoviral vectors have been used extensively for gene therapy. However, efficient infection of cells requires expression of the coxsackie-adenoviral receptor (CAR). Many tumor cells lack adequate expression of CAR and, hence, are not good targets for adenoviral based vectors. We have developed a unique nanoparticle (Epi-039) that can be used to efficiently introduce adenoviral vectors into tumor cells that have low or no CAR expression. We used the CAR-negative 4T1 mammary carcinoma model system, which represents a typical triple-negative breast cancer cell line (ER−, PR−, HER2−) and which is refractory to adenoviral infection to demonstrate effective transduction of an encapsulated oncolytic adenovirus. The adenovirus that was used is called AdAPT-001. This armed oncolytic virus, which is currently in a phase I/II clinical trial called BETA PRIME for the treatment of refractory cancers, expresses a TGFb receptor trap to neutralize the immunosuppressive cytokine, TGF beta. Overexpression of TGF-beta positively correlates with metastasis in breast carcinoma and thus confers a poorer prognosis. In this study, the unique Epi-039 nanoparticle carrying AdAPT-001 not only significantly enhanced the transduction efficiency of AdAPT-001 but also protected it from neutralization by natural antibodies in human whole blood. Accordingly, we demonstrate a significant increase (P value= 0.0029) in the expression of green fluorescent protein (GFP) in CAR-negative 4T1 cells infected with the encapsulated AdAPT-001 adenovirus but not the unencapsulated AdAPT-001 adenovirus. Additional in vivo studies using nanoparticle encapsulated adenoviral vectors including AdAPT-001 to treat breast cancer are underway for rapid translation to the clinic.

Citation Format: Tony Reid, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, Christopher Larson. Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial [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 P3-07-20.
Abstract P3-08-09: Development and molecular characterization of hard-to-treat breast cancer pre-clinical models to enhance precision medicine
Authors: Kuasne Hellen , fortier Anne-Marie , Busque Sandrine , Mathien Simon , Savage Paul , Ramirez Constanza Martinez , Monast Anie , Soleinova Margarita , Omeroglu Atilla , Asselah Jamil , Bouganim Nathaniel , Meterissian Sarkis , Basik Mark , Park Morag
Published: March 2023

Invasive breast carcinoma is a combination of heterogeneous diseases with distinct molecular and clinical features. Some subsets of breast cancer present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare breast histologies. Previously, we developed a unique resource of 37 hard-to-treat breast cancer patient-derived xenografts (PDX). This set included mainly triple negative breast cancer (TNBC) patients that presented poor response to neoadjuvant chemotherapies (Savage et al. 2020 - PMID: 32546838). PDXs accurately reproduce the molecular heterogeneity of the primary tumors and show that multi-drug chemoresistance was retained upon xenotransplantation. Here, we present the characterization of PDX 3-dimensional cultures organoids (8) and PDX derived epithelial cell lines (11). Using single-cell RNAseq we showed that an organoid cultured for several passages (P8) maintained the heterogeneity of the matched PDX. Although in different proportions, all cancer cell populations found in the PDX were retained in matched organoids supporting that organoids are suitable models that recapitulates the tumor heterogeneity and are therefore a suitable model for drug screening. Among our new PDXs models (30), we have developed four PDXs from rare metaplastic breast cancers (MpBC), an aggressive subtype of breast cancer that present the poorest response to standard of care chemotherapy. We also developed one male breast cancer PDX with matched organoid. Omic analysis on our pre-clinical models and patient primary tumor and metastasis will inform development of therapeutic opportunities. This molecular information will guide selection of compounds that will be validated using our high throughput organoid drug screening pipeline. This will allow rapid screens of thousands of approved drugs, enhancing drug repurposing with potential for rapid clinical translation. The combined use of 3D tumor organoids and PDXs, is an important opportunity poised to transform identification of new therapeutic options for hard-to-treat lethal breast cancers.

Citation Format: Hellen Kuasne, Anne-Marie fortier, Sandrine Busque, Simon Mathien, Paul Savage, Constanza Martinez Ramirez, Anie Monast, Margarita Soleinova, Atilla Omeroglu, Jamil Asselah, Nathaniel Bouganim, Sarkis Meterissian, Mark Basik, Morag Park. Development and molecular characterization of hard-to-treat breast cancer pre-clinical models to enhance precision medicine [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 P3-08-09.
Abstract P3-09-02: Pateint Derived Breast Cancer Organoids as a Model for Testing Personalized Therapies
Authors: Wajih Nadeem , Erali Richard , Forsythe Steven , Soker Shay , Votanopoulos Konstantinos
Published: March 2023

Introduction: Breast cancer is one of the most frequently diagnosed cancer in women with a high mortality rate. More than 20 different subtypes of breast cancer are identified. Advancement in patient-derived organoid technology makes it possible to preserve cellular, structural, and tissue microenvironment which mimics the tissue in vivo. Method: We developed patient derived breast organoids both from normal and cancer biopsies recapitulate the structure of breast tissue. Breast biopsies were enzymatically digested to yield a single cell suspension. About 1 × 105 cells were encapsulated in a specialized hydrogel mixture. Immune enhanced breast tumor organoids (iTOs) included 2 × 105 patient matched PMBCs. Results: Histological analyses of the breast organoids shows the characteristics of the breast tissue with well-defined acini in H&E. In tumor organoids acini were somewhat perturbed compared to normal breast organoids. Immuno-fluorescence staining shows the expression of breast biomarkers including EGF receptor 2 (HER2), Progesterone receptor (PR), Estrogen receptor (ER). Zona occludin 1 and 2 and keratin 19 expression in luminal cells and expression of Keratin 14 and P63 in basal cells suggested correct polarization in the organoids. Immunofluorescence staining of (iTOs), with T cell markers including CD3, CD4, and CD8 indicated that immune cells remained viable in the iTOs. Drug responses to Doxorubicin, Paclitaxel and a combination of Doxorubicin-Paclitaxel showed significant inhibition of cell growth in normal and tumor organoids (p< 0.04, n=11) except for Paclitaxel failed to inhibit tumor cell growth. However, immunotherapy with nivolumab (anti PD-1) showed no significant effect on cell growth. Conclusions: Pateint Derived Breast cancer organoids recapitulate the histological features of breast tissue in culture and response to chemotherapies. In the future, patient-derived tumor organoids can provide a platform for personalized medicine.

Citation Format: Nadeem Wajih, Richard Erali, Steven Forsythe, Shay Soker, Konstantinos Votanopoulos. Pateint Derived Breast Cancer Organoids as a Model for Testing Personalized Therapies [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 P3-09-02.
Abstract P4-01-32: BAT8008, a novel Trop-2 ADC with strong bystander effect, for the treatment of Trop-2 positive cancer
Authors: Mei Xingxing , Tang Weijia , Zhou Xin , Qi Xuekang , Mai Siqi , Zhong Zhi , Li Shuoxu , Fan Jianjun , Gan Jirong , Tan Binghua , Qi Yao , Guo Yanling , Yu Jin-Chen , Li Shengfeng
Published: March 2023

Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Elevated expression of TROP-2 is often associated with tumor invasion/aggression, progression, and metastasis. Efficacy of anti-TROP2 ADC have been demonstrated in clinical trials for both TNBC (triple negative breast cancer) and HR+/HER2- breast cancer. We have developed a novel Trop-2 ADC with strong bystander killing effect, BAT8008, which consists of an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 6. BAT8008 demonstrated potent in vitro cell growth inhibitory activity to Trop2-positive cells with IC50 values of < 1 nM. In an in vitro bystander killing assay, proliferation of Trop-2-negative cells was potently inhibited by addition/transfer of culture medium of BAT8008-treated Trop-2-positive cells, but not that of BAT8008-treated Trop-2-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.1% of the payload was released from BAT8008 when incubated with human or monkey plasma for 7 days in 37°C, suggesting the stability of BAT8008 in blood circulation. Single dose of BAT8008 at 1 and 2.5 mg/kg could inhibit 73% and 81% tumor growth in the Trop-2-positive MDA-MB-468 and MX-1 xenograft mice model, respectively. BAT8008 also demonstrated superior tumor inhibition activity than a modified ADC using Daiichi’s ADC technology or Trodelvy in a pancreatic BxPC-3 xenograft mice model. In addition, BAT8008 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of at least 25 mg/kg when dosed once every two weeks for 3 times. Together these results indicate that BAT8008 could potentially provide a therapeutic benefit to treat TROP2-positive breast cancers in clinical trial.

Citation Format: Xingxing Mei, Weijia Tang, Xin Zhou, Xuekang Qi, Siqi Mai, Zhi Zhong, Shuoxu Li, Jianjun Fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Jin-Chen Yu, Shengfeng Li. BAT8008, a novel Trop-2 ADC with strong bystander effect, for the treatment of Trop-2 positive cancer [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 P4-01-32.
Abstract P4-03-16: Association between tamoxifen and the incidence of cataract in ductal carcinoma in situ patients
Authors: Kim Dooreh , Park Woo-Chan , Jeon Soyoung , Lee Hye Sun , Yoon Chang Ik
Published: March 2023

Background Tamoxifen is used to improve oncologic outcomes in a hormone receptor-positive breast cancer. High-dose tamoxifen induced ocular toxicities, and regular dose of tamoxifen is known to increase the risk of cataracts in landmark studies. The current study’s objective is to review the incidence of cataracts in ductal carcinoma in situ (DCIS) patients who received adjuvant tamoxifen treatment, which can exclude the effect of other treatment modalities such as chemotherapy and target therapy. Method Data were obtained from the National Health Insurance claims database of the Health Insurance Review and Assessment Service in South Korea. Patients diagnosed with DCIS were sorted and retrospectively reviewed for the incidence of cataracts. The primary study outcome was the incidence of cataracts according to tamoxifen, and the incidence of cataracts was defined by concomitant diagnostic and behavioral code based on International Code of Disease, 10th revision. Results A total of 12,032 patients diagnosed with DCIS and received breast surgery from 2009 to 2015 were cut down to 4,759 patients, excluding those who already had cataracts, malignancies, or had developed cataracts within a year of breast cancer surgery. There were 3,037 patients who received tamoxifen and 1,722 patients who did not, median age of 49 years old. The incidence of cataracts was similar according to the use of tamoxifen, 7.6% and 7.7% respectively. The risk of developing cataracts did not increase with or without tamoxifen, even in the group who received adjuvant tamoxifen for more than two years (HR 0.978, 95% CI 0.782-1.222, p=0.843). The findings were consistent after propensity score matching (HR 1.072, 95% CI 0.829-1.388, p=0.595). Conclusions In a nationwide cohort study, the risk of cataracts in DCIS patients is similar whether the tamoxifen is used or not.

Citation Format: Dooreh Kim, Woo-Chan Park, Soyoung Jeon, Hye Sun Lee, Chang Ik Yoon. Association between tamoxifen and the incidence of cataract in ductal carcinoma in situ patients [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 P4-03-16.
Abstract P4-06-08: HER2-protein expression is a predictive marker for treatment response in patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with dual HER2-blockade
Authors: Bae Soong June , Jang Ji Soo , Kook Yoonwon , Baek Seung Ho , Kim Jee Hung , Ahn Sung Gwe , Jeong Joon
Published: March 2023

Background In HER2-positive breast cancer, pathologic complete response (pCR) has been known to be a surrogate marker for favorable prognosis after neoadjuvant chemotherapy. We aimed to identify the clinico-pathologic factors related to pCR in patients with HER2-positive breast cancer treated with neoadjuvant dual HER2-targeted therapy. Methods Two-hundred ninty-five patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) were included in this retrospective analysis. We assessed the association between age, clinical T, N stage, pathologic factors such as histologic grade, hormone receptor (HR), tumor-infiltrating lymphocytes, the membranous expression of HER2 protein evaluated by immunohistochemistry (IHC) and pCR. The fluorescent in situ hybridization (FISH) was performed in a tumor with HER2 score of 2+. Results Of the 295 patients, 195 (66.1%) achieved pCR (ypT0/is and ypN0). Besides, 240 (81.4%) patients were HER2 score of 3+, and 55 (18.6%) patients were HER2 score of 2+. The pCR was frequently observed in patients with HER2 score of 3+ (64 of 176 [73.3%]) than in those with HER2 score of 2+ (19 of 55 [34.5%]), regardless of HR status. After adjusting other clinicopathologic factors, the high HER2 protein expression was only an independent factor for pCR (adjusted OR 3.85, 95% CI, 1.66-8.91, p=0.002). Conclusions Our results suggest that high expression of HER2 protein assessed by IHC is important in predicting neoadjuvant TCHP response in HER2-positive breast cancer.

Citation Format: Soong June Bae, Ji Soo Jang, Yoonwon Kook, Seung Ho Baek, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. HER2-protein expression is a predictive marker for treatment response in patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with dual HER2-blockade [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 P4-06-08.
Abstract P4-07-44: Association between tissue mobilization with physical exercise and physical exercise alone in patients with axillary web syndrome who underwent breast cancer surgery
Authors: Figueira Patricia V. , Haddad Cinira , de Almeida Rizzi Samantha K. Lopes , Estevao Amanda , Elias Simone , Facina Gil , Nazário Afonso
Published: March 2023

Introduction: Axillary web syndrome (AWS) is a complication in women with breast cancer and occurs immediately after axillary surgery. It is characterized by pain, limited shoulder range of motion (ROM), and presence of cords. Objectives: This study aimed to evaluate the impact of physical therapy interventions, such as physical exercise with tissue mobilization and exercise alone. Methods: A randomized clinical trial was conducted at the Divison of Breast Cancer disease of the Universidade Federal de São Paulo. Seventy-three women with AWS were randomized into the mobilization (ME) group (N=37) and exercise (E) group (N=36) and followed up for 3 months after breast cancer surgery. Both groups were provided with specific guidelines for performing regular shoulder exercise at home, while tissue mobilization was performed in a specific group with a maximum of six sessions, according to the patient’s need. ROM, pain, and presence of cords were evaluated in each postoperative period (PO). Results: In both treatment groups, at the end of 90 days, improvement in flexion was observed as well as less pain and number of cords. In terms of abduction, the E group was better than the ME group. Conclusions: Physical exercise after breast cancer surgery is extremely important for functional recovery, resumption of activities of daily living, improvement of pain, and reduction in the number of cords. Tissue mobilization appears as an adjunct for causing a more immediate improvement in ROM, pain, and presence of cords, but at times not sustaining the gains for the following PO. Keywords: breast neoplasms, axillary web syndrome, physical exercise, articular range of motion, pain

Citation Format: Patricia V. Figueira, Cinira Haddad, Samantha K. Lopes de Almeida Rizzi, Amanda Estevao, Simone Elias, Gil Facina, Afonso Nazário. Association between tissue mobilization with physical exercise and physical exercise alone in patients with axillary web syndrome who underwent breast cancer surgery [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 P4-07-44.
Abstract P4-07-57: Outcomes of Triple-Negative Breast Cancer In Older Versus Younger Women
Authors: Munir Asma , Khawaja Saira , Khan Sohail , Sharaiha Yousuf , Huws Anita M.
Published: March 2023

Background: Triple-negative breast cancer (TNBC) is an aggressive disease characterized by lack of targeted therapy; main-stay of treatment being limited to surgery and chemotherapy. Older patients with TNBC are often underrepresented in the clinical trials, due to competing mortality risks. This study aims to assess the treatment and outcomes of triple negative breast cancer (TNBC) in older women relative to younger women. Methods: This was a retrospective cohort study of patients who presented with primary TNBC, age 34-94 years; stage I-III from Jan 1, 2013 to Dec 31, 2015. Patients’ demographics, clinical characteristics, treatment and outcomes were retrieved from the CANISC Register and individual patient (N=88). Breast cancer-specific survival (BCSS) was estimated by using Kaplan–Meier method, and adjusted for age, tumor size, tumor grade, nodal status and chemotherapy, using SPSS-19. Results: Fifty-one patients were less than 70 years old (57.9%) and 37 were 70 years and older (42.1%). There was no difference in the stage at presentation (stage I: 43% vs. 35%; stage 2: 49% vs. 49%; stage 3: 8% vs. 11%; P=.061). Older patients were less often treated with adjuvant chemotherapy (75% vs. 24%; P< 0.001). Mean follow-up was 48 months. Five-year BCSS was significantly poor for older patients (54% vs. 75%, P=.032). 5-year overall survival was also significantly worse for patients who did not receive adjuvant chemotherapy (50% vs. 88% P =0< 021). Conclusions: Overall survival in triple negative breast cancer is much worse in older women as compared to younger women and there is a significant benefit with adjuvant chemotherapy.

Citation Format: Asma Munir, Saira Khawaja, Sohail Khan, Yousuf Sharaiha, Anita M. Huws. Outcomes of Triple-Negative Breast Cancer In Older Versus Younger Women [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 P4-07-57.
Abstract P4-08-25: Unravelling the role of human endogenous retrovirus K (HERV-K) in inducible nitric oxide synthase (iNOS) mediated triple negative breast cancer progression
Authors: Bhattacharyya Dibyangana , Dervan Eoin , Glynn Sharon , Callagy Grace
Published: March 2023

Human endogenous retrovirus K (HERV-K) belongs to a family of endogenous retroviruses that are present in our genome with similarities to present day exogenous retroviruses. This virus can express several proteins but our knowledge of HERV-K expression in human cancers is mainly limited to the envelope (Env) protein. Elevated HERV-K env protein expression has been shown in breast cancer both in in vitro and in vivo studies. This project aimed to decipher mechanisms of HERV-K induction in triple negative breast cancer (TNBC), and the impact of HERV-K targeting shRNA mediated knockdown on TNBC characteristics including cell migration, invasion and proliferative capacity in 2D and 3D cell culture models. Our results show that a role for inducible nitric oxide synthase (iNOS) in the induction of HERV-K in TNBC cell lines. RNA seq and bioinformatics analysis was performed to identify key molecular processes regulated by HERV-K and nitric oxide (NO) in MDA-MB-231 TNBC cells. Reduced rates of migration, invasion and proliferation in HERV-K knockdowns points towards the essential role of HERV-K in tumorigenesis and metastasis. HERV-K knockdown also modulated key gene expression signatures traditionally associated with the basal and mesenchymal phenotypes in breast cancer, cellular senescence and MHC class gene regulation. The co-expression of iNOS and HERV-K was assessed in over 150 TNBC cases and the association with patient outcomes assessed. Taken together, our findings indicate that NO and HERV-K may be a useful molecular target for the treatment of TNBC.

Citation Format: Dibyangana Bhattacharyya, Eoin Dervan, Sharon Glynn, Grace Callagy. Unravelling the role of human endogenous retrovirus K (HERV-K) in inducible nitric oxide synthase (iNOS) mediated triple negative breast cancer progression [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 P4-08-25.
Abstract P5-02-52: Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis
Authors: Shi Qiyun , Xuhong Juncheng , Tian Hao , Zhang Yi , Jiang Jun , Qi Xiaowei
Published: March 2023

Background: PIK3CA mutations is one of the most frequent gene alterations in breast cancers, which was reported to be related to the treatment response of anti-HER2 regimens. However, the relationship between PIK3CA mutations and treatment response of a tyrosine kinase inhibitors (TKIs) is still unclear. We thus conducted a systemic review and meta-analysis to investigate the predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with TKIs. Methods: The following databases were searched from inception to July 2022: Medline, Embase and the Cochrane Library. Abstracts from conferences were also reviewed for inclusion. The critical information was extracted from eligible studies. Results: A total of 16 reports including 17 studies were assessed for eligibility, enrolling 1706 patients. Ten studies including 902 patients were in the neoadjuvant setting, the pCR rate is significantly higher in PIK3CA wild-type (WT) patients than in mutated-type (MT) patients (OR = 0.45; 95% CI: 0.31-0.65; P< 0.001). Seven studies including 804 patients were in the metastatic setting, the pooled objective response rate (ORR) is significantly higher in PIK3CA WT patients than in MT patients (OR = 0.40; 95% CI: 0.23-0.70; P = 0.001), and similarly, the clinical benefit rate (CBR) in WT patients is also higher (OR = 0.43; 95% CI: 0.19-0.98; P=0.045). A total of 4 metastasis studies reported progression free survival (PFS), and 2 of them reported overall survival (OS), revealing a marginally significant relationship between PIK3CA mutation and worse PFS (HR = 0.82; 95% CI: 0.67-1.00; P=0.052) and OS (HR=0.63, 95%CI:0.39-1.02; P=0.062). No evidence of publication bias was found in both the neoadjuvant setting and metastatic setting. Conclusion: Our findings indicate that PIK3CA mutations is significantly associated with a lower rate of pCR when treated with TKI-containing regimens in neoadjuvant chemotherapy of early-stage HER2-positive breast cancer, and is significantly associated with lower ORR and CBR in metastatic HER2-positive breast cancer.

Citation Format: Qiyun Shi, Juncheng Xuhong, Hao Tian, Yi Zhang, Jun Jiang, Xiaowei Qi. Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis [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 P5-02-52.
Abstract P5-05-09: Multianalyte liquid biopsy to aid the diagnostic workup of breast cancer
Authors: Shishido Stephanie , Kuhn Peter , Mason Jeremy , Hicks James , Nevarez Rafael , Matsumoto Nicholas , Kolatkar Anand , Velasco Carmen Ruiz , Anderson Amanda , Kidd Michael , Wilkinson Kathy , Hwang E Shelley , Lu Janice , Nieva Jorge , Higa Nikki , Naghdloo Amin , Hart Olivia , Setayesh Sonia Maryam
Published: March 2023

Breast cancer (BC) affects 1 in every 8 women in the United States and is currently the most prevalent cancer worldwide. Precise staging at diagnosis and prognosis are essential components for the clinical management of BC patients. The liquid biopsy (LBx) has promising applications in cancer screening and early diagnosis ultimately leading to better survival results and less disease burden. In this study, we evaluated the feasibility of the high-definition single cell assay (HDSCA) LBx platform to stratify disease states (early- and late-stage BC) and normal donors using peripheral blood samples. In the HDSCA3.0 workflow, both common white blood cells (WBCs) and rare cells, including circulating tumor cells (CTCs), EMT and platelet-coated cells, plus acellular structures are identified and classified computationally from scanned immunofluorescent images. This comprehensive LBx approach provides a quantitative landscape view of each individual case. In a striking example of the insight provided by HDSCA, we compared LBx results for early-stage and late-stage BC patients with two independent cohorts of normal donors to show the utility of a blood draw as a source of biomarkers for early-stage cancer detection. As expected, CTCs were detected at a higher level in late-stage patients, compared to either the early-stage or normal donors. Surprisingly, however, we observed a significantly higher incidence of tumor-associated large extracellular vesicles (LEVs) in the early-stage patients, compared to the other two groups. A patient-level classification model was able to correctly classifying LBx profiles as normal, early, or late with LEV enumeration as the strongest predictor, followed by epi.CTC enumeration. We will present a reproducible LBx profile of rare cells and LEVs of early-stage disease compared to late-stage BC and normal donors with high accuracy, allowing for robust stratification. Our findings illustrate the feasibility of the LBx to assess early disease states prior to clinically defined metastasis, stratified from normal donors, highlighting the general consideration of the liquid biopsy for the diagnostic work-up and potentially screening.

Citation Format: Stephanie Shishido, Peter Kuhn, Jeremy Mason, James Hicks, Rafael Nevarez, Nicholas Matsumoto, Anand Kolatkar, Carmen Ruiz Velasco, Amanda Anderson, Michael Kidd, Kathy Wilkinson, E Shelley Hwang, Janice Lu, Jorge Nieva, Nikki Higa, Amin Naghdloo, Olivia Hart, Sonia Maryam Setayesh. Multianalyte liquid biopsy to aid the diagnostic workup of breast cancer [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 P5-05-09.
Abstract P5-09-05: A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial)
Authors: shan zhen , shao nan , zhang xiaoling , shi huijuan , zheng yanling , luo jia , zhen tiantian , chen ruping , Lin Ying
Published: March 2023

Background: Tucidinostat (formerly known as chidamide) plus exemestane is approved for postmenopausal patients with advanced, hormone receptor-positive breast cancer. We evaluated the efficacy and safety of tucidinostat plus exemestane as the neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: NeoTEE is an open-label, single-center, phase II study. Patients with HR-positive, HER2-negative and stage II/III breast cancer were enrolled at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients received 25 mg oral exemestane once daily for 2 weeks followed by 30 mg oral tucidinostat twice weekly in combination with 25mg oral exemestane once daily for 24 weeks. GnRHa was used for premenopausal patients. Endpoints assessed here included objective response rate (ORR), complete cell cycle arrest (CCCA, Ki-67≤2.7%) at surgery, disease control rate (DCR), pathological complete remission (pCR) and safety. Results: Between July 2020 and July 2022, 26 patients were enrolled, of whom 24 were evaluable for response per RECIST 1.1 criteria. Partial response (PR) was observed in 18 patients, with an ORR of 75% (18/24). The DCR was 100%. Of the 14 patients with surgery, one patient achieved pCR and 8 patients were exempt from postoperative adjuvant chemotherapy. CCCA at surgery was 64.3% (9/14). The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs occurred in 8 of 26 patients, the most common were neutropenia 19.2%, leukopenia 7.7%, anemia 3.8%, ALT increased 3.8%, pneumonitis 3.8%. Only 1 patient experienced grade 4 neutropenia. Grade 3/4 neutropenia recovered after dose reduction or discontinuation of tucidinostat. No patient received G-CSF. Conclusions: Tucidinostat combined with exemestane was well tolerated and demonstrated meaningful responses in neoadjuvant setting for women with early HR+/HER2- breast cancer. Further investigation is warranted. Clinical trial information: NCT04465097.

Citation Format: zhen shan, nan shao, xiaoling zhang, huijuan shi, yanling zheng, jia luo, tiantian zhen, ruping chen, Ying Lin. A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial) [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 P5-09-05.
Abstract P5-11-04: Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC
Authors: Mego Michal , Hadzega Dominik , Minarik Gabriel , Soltysova Andrea , Nemcova Petra , Kalavska Katarina , Karaba Marian , Benca Juraj , Sedlackova Tatiana , Pindak Daniel , Klucar Lubos
Published: March 2023

Background: Circulating tumor cells (CTC) with phenotype of epithelial-mesenchymal transition (CTC_EMT) represent novel subpopulation of CTC associated with inferior outcome in primary breast cancer (PBC). However, molecular characterization of primary tumors associated with this CTC subpopulation is lacking. The aim of this study was to identify signaling pathways associated with presence of CTC_EMT in PBC patients using a comprehensive genomics approach. Methods: This translational study included 17 patients with PBC and 5 donors of normal breast tissue. CTC_EMT were detected before surgery by quantitative RT-PCR assay for expression of epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted, in parallel, from fresh frozen primary tumor and whole-trancriptome profiles were obtained using RNA sequencing and additionally mRNAs profiles by microarray. Genes expressions were further validated by qRT-PCR. Results: Analyzing RNA sequencing and microarray data, we found set of genes differentially expressed in absence or presence of CTC_EMT in PBC. We identified 157 genes differentially expressed in CTC_EMT phenotype compared to patients with non-detectable CTC. Namely, keratin family is represented by genes KRT5, KRT14, KRT17. Gene ontologies related to membrane structure or communication and immunology appears to be involved in CTC-related processes, pathways related to cell junction and various signaling pathways including PI3K and Ras-signaling appear to be significant in processes leading to CTC EMT presence. Conclusions: We suspect multiple genes of having a role in primary tumour processes leading to CTC EMT production in breast cancer patients. Data suggest, that PI3K & Ras-signalling and pathways related to cell junction are the key pathways for changes inside of primary tumour tissue between CTC EMT and CTC- phenotype of breast cancer patients. We propose, additional study with single-cell resolution is needed for better understanding of the processes.

Citation Format: Michal Mego, Dominik Hadzega, Gabriel Minarik, Andrea Soltysova, Petra Nemcova, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Daniel Pindak, Lubos Klucar. Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC [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 P5-11-04.
Abstract P5-12-06: Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients
Authors: Liao Ning , Cao Li , Zhang Guochun , Wang Junyun , Yang Airong , Wang Yulei , Li Kai , Wen Lingzhu , Ren Chongyang , Jia Minghan , Li Cheukfai , Mok Hsiaopei , Chen Bo , Lai Jianguo , Xiao Weikai
Published: March 2023

Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear.

Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations.

Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1).

Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy.

Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers

Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [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 P5-12-06.
Abstract P6-01-28: Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
Authors: Alblihy Adel , Shoqafi Ahmed
Published: March 2023

The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.

Citation Format: Ahmed Shoqafi. Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers [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 P6-01-28.
Abstract P6-01-44: Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy
Authors: Ho Peh Joo , Khng Alexis Jiaying , Tan Benita Kiat Tee , Tan Ern Yu , Lim Geok hoon , Tan Su-Ming , Tan Veronique Kiak Mien , Lim Elaine Hsuen , Hartman Mikael , Li Jingmei
Published: March 2023

Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in treated patients. Methods We performed DNAm analysis in 1,244 and 897 breast cancer patients treated and not treated by adjuvant chemotherapy using the Illumina MethylationEPIC array (1,804 blood, 337 saliva). DNAm changes of 620,095 individual CpGs and 41,581 promoters were evaluated using linear regression models, adjusting for age at diagnosis, ethnicity, years between sample collection and diagnosis and cell-type heterogeneity. Results from datasets normalized separately were combined by meta-analysis (random effects model). Gene set enrichment analyses were conducted to identify key processes or pathways associated with chemotherapy treatment. Results A total of 425 differentially methylated CpGs and 20 promoters were significantly associated with chemotherapy treatment (p< 5e-8). Enriched gene sets among 3,495 chemotherapy-associated promoters (unadjusted p< 0.05, preranked by Z scores) included three suppressed Gene Ontology (GO) terms that survived Bonferroni correction (GO:0002376, immune system process; GO:0009605, response to external stimulus; and GO:1903034: regulation of response to wounding). Using meta-analysis regression coefficients for all promoters as a ranking metric, olfactory transduction (KEGG, hsa04740) was found to be significantly suppressed (unadjusted p=6.38e-06, adjusted p=0.002). Taste transduction (hsa04742, unadjusted p=1.73e-03, adjusted p=0.565) was the next most significantly suppressed pathway. Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy treatment could affect immune response, wound healing and changes in the perceptions of smell and taste.

Citation Format: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Ern Yu Tan, Geok hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Elaine Hsuen Lim, Mikael Hartman, Jingmei Li. Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy [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 P6-01-44.
Abstract P6-01-45: Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer
Authors: Liu Chun-Yu , Huang Chi-Cheng , Tsai Yi-Fang , Chao Ta-Chung , Lin Yen-Shu , Feng Chin-Jung , Lai Jiun-I , Chen Ji-Lin , Chen Yen-Jen , Chiu Jen-Hwey , Hsu Chih-Yi , Tseng Ling-Ming
Published: March 2023

Introduction: Neoadjuvant chemotherapy, one of systemic treatment of breast cancer, is employed for downstaging of inoperable tumor. Pathological complete response (pCR) after neoadjuvant chemotherapy is associated with good prognosis for breast cancer. The critical role of anti-tumor immune responses in conventional chemotherapy and targeted therapy has been reported. However, the pCR-associated immune genes are still ambiguous. Materials and Methods: Thirty-seven primary breast cancer patients receiving neoadjuvant chemotherapy as the first-line treatment for breast cancer were recruited in this VGH-TAYLOR study (NCT04626440). Total RNA of fresh tumor tissues was isolated and then reverse transcribed into cDNA. The Oncomine Immune Response Research Assay was employed for examination of immune-related gene expressions. In silico analyses were performed using the public databases, including Gene Expression Omnibus, Kaplan-Meier plotter, ROC Plotter, Cancer Therapeutics Response Portal, and The Cancer Genome Atlas. Results: Patients achieved a pCR were associated with lower tumor stage and HER2 expression. The next-generation sequencing-based analysis showed that the expression of eight genes were higher in tissues of patients with pCR than non-pCR, including KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4. The 8-gene score was associated with better recurrence-free survival in patients receiving chemotherapy. Data from an ROC Plotter database showed that higher expressions of IGJ, CD69, and MS4A1 in patients respond to neoadjuvant chemotherapy compared to non-responders. In silico analysis revealed that the negative correlation between pCR-associated gene expressions and IC50 values suggesting the gene high expression was sensitive to the drugs. Moreover, the levels of pCR-associated gene were downregulated in breast tumor tissues and positively correlated with immune cell infiltrations. Conclusion: We identified eight immune genes which were associated with better prognosis and drug responses. The 8-gene score may serve as a prognostic marker for breast cancer patients who receiving neoadjuvant chemotherapy.

Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Yi-Fang Tsai, Ta-Chung Chao, Yen-Shu Lin, Chin-Jung Feng, Jiun-I Lai, Ji-Lin Chen, Yen-Jen Chen, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer [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 P6-01-45.