bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-13-04: Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers
Authors: Boyd David , Harrell Chuck
Published: March 2023

Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers David C. Boyd1,2, Amy L. Olex3, Tess Leftwich1, Nicole Hairr1, Alex K. Duong1, Narmeen S. Rashid1,3, Mohammad A Alzubi1,2, Holly Byers1, Aaron D. Valentine1, Julia E. Altman1, Emily Zboril1, Jacqueline M. Grible1, Madelyn Esquivel1, Scott A. Turner1, Andrea Ferreira-Gonzalez1, Mikhail G. Dozmorov5, J. Chuck Harrell1,2,6 1Department of Pathology, Virginia Commonwealth University; 2Integrative Life Sciences Program, VCU; 3Wright Center for Clinical and Translational Research, VCU; 4Department of Biology, University of Richmond; 5Department of Biostatistics, VCU; 6Massey Cancer Center, VCU. There is an urgent need for new therapeutic options for basal-like Triple Negative Breast Cancers (TNBC). To mirror the NCI-ComboMATCH study, and identify new synergistic drug combinations, we analyzed a set of 20 breast cancer patient-derived xenografts and 14 cell lines to identify targetable targets in each model. The Oncomine Comprehensive Assay v3 was performed to assess 161 genes for hotspot mutations, focal copy number variants, amplification/deletions, and RNA-fusion genes. Next, each PDX and their isogenic drug-resistant sublines were analyzed with bulk RNA-sequencing (217 samples) and cell single-cell RNA-sequencing (~100,000 cells). Of all NCI-MATCH defined targetable mutations, 37% of the models contained pathogenic PIK3CA amplifications or mutations. PIK3CA is one of the most common oncogenic aberrations identified in patients and the PI3K pathway is overactive in the majority of TNBCs, therefore we sought to target it across all models and identify the most efficacious synergistic drug partner. Short-term cultures of each PDX model were screened with a library of >1,000 FDA-approved/experimental drugs to identify compounds that were cytotoxic. Synergistic drug screens were then performed with each drug in combination with the PI3K inhibitor byl-719 (alpelisib) a current standard-of-care drug used for PI3K mutant ER+ disease. Synergism was identified using coefficient of drug interaction (CDI) calculations and 10 drugs were identified as synergistic across several models. Using several criteria, including clinical status and pathway analysis, 3 drugs were selected for CompuSyn-based synergism testing and each was confirmed to be synergistic in vitro. Testing with in vivo models of each drug combination has thus far confirmed that each is synergistic per CDI metrics. Those combinations are currently being tested for efficacy in the metastatic setting with a set of basal-like PDXs.

Citation Format: David Boyd, Chuck Harrell. Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative 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 P1-13-04.
Abstract P1-13-12: Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative breast cancer
Authors: Terrero David , Tiwari Amit , Raman Dayanidhi
Published: March 2023

The development of drug resistance is a primary cause of chemotherapy failure in the treatment of triple-negative breast cancer (TNBC). Some cancer cells are resistant to drugs with unrelated structures and mechanisms of action, a phenomenon known as multidrug resistance (MDR). Although taxanes such as docetaxel and paclitaxel are effective against non-metastatic and metastatic TNBC and other types of breast cancer, they eventually become ineffective due to development of drug resistance. Mitochondrial dynamics has gained significant attention as a means to treat MDR and non-MDR cancers. Mitochondrial dynamics determine the number, shape, and location of mitochondria within cells, which are fundamental to the health of the cell. Among its key components is the mitochondrial fission-promoting dynamin-related protein 1 (Drp1). There is mounting evidence indicating that both Drp1 and its phosphorylated form promote cancer survival, resistance to apoptosis, and chemoresistance. We observed increased phosphorylation of Drp1 at Ser616 as well as phosphorylation of its upstream kinase ERK1/2 in TNBC lines SUM159PT and its paclitaxel-resistant derivative that we developed called SUM159PT/PAC200 that displays more than an 80-fold increase in resistance to paclitaxel. Using CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in both lines. When Drp1 is genetically ablated, paclitaxel resistance in SUM159PT/PAC200 was significantly reversed. Furthermore, proliferation, migration, and invasion capabilities were decreased in both parental and paclitaxel-resistant Drp1 knockout lines. In SUM159PT/PAC200 Drp1-KO cells, a mesenchymal to epithelial transition (MET) was observed as indicated by downregulation of mesenchymal markers such as N-cadherin and -catenin, and upregulation of the epithelial marker ZO-1. Interestingly, Drp1 knockout halted the ability of SUM159PT/PAC200 to form colonies in soft agar. SUM159PT/PAC200 cells strongly express the MDR pump P-glycoprotein (ABCB1), to which paclitaxel is a known substrate, and genetically targeting Drp1 reduced the expression to almost undetectable levels. Taken together, these findings suggest that Drp1 is both a resistance factor and a key protein in breast cancer proliferation and dissemination, making it a promising actionable molecular target in the treatment of TNBC. Further studies are in progress to understand the role of Drp1 in the development and maintenance of MDR phenotype, proliferation, and invasion.

Citation Format: David Terrero, Amit Tiwari, Dayanidhi Raman. Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative 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 P1-13-12.
Abstract P1-13-23: Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft
Authors: Dozmorov Mikhail , Marshall Maggie , Rashid Narmeen , Grible Jacqueline , Valentine Aaron D. , Olex Amy , Murthy Kavita , Chakraborty Abhijit , Reyna Joaquin , Figueroa Daniela Salgado , Lee Da-Inn , Baur Brittany , Roy Sushmita , Ay Ferhat , Harrell Chuck
Published: March 2023

Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2Mb) interactions, chromatin looping, formation of topologically associating domains (TAD), chromatin state switching into a more active state, and amplification of ATP-binding cassette (ABC) transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.

Citation Format: Mikhail Dozmorov, Maggie Marshall, Narmeen Rashid, Jacqueline Grible, Aaron D. Valentine, Amy Olex, Kavita Murthy, Abhijit Chakraborty, Joaquin Reyna, Daniela Salgado Figueroa, Da-Inn Lee, Brittany Baur, Sushmita Roy, Ferhat Ay, Chuck Harrell. Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [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 P1-13-23.
Abstract P2-06-02: A randomized controlled trial of soy isoflavone intake on mammographic density among Malaysian women
Authors: Rajaram Nadia , Yap Beverley , Eriksson Mikael , Mariapun Shivaani , Tan Lee Mei , Saat Hamizah , Ho Evelyn , Taib Nur Aishah Mohd , Khor Geok Lin , Yip Cheng Har , Ho Weang Kee , Hall Per , Teo Soo Hwang
Published: March 2023

Introduction: Soy intake is associated with lower breast cancer risk in observational studies of Asian women, but clinical trials of soy isoflavone (ISF) supplements report no effect on biomarkers of breast cancer risk among Caucasian women. To date, there are no such trials among Asian women living in Asia. We conducted a three-armed, randomized controlled trial (RCT) to assess the effects of one-year intervention of soy isoflavone supplements (100mg/day) or soy isoflavones through diet (50mg/day) on mammographic density (MD) change among peri- and postmenopausal Malaysian women. Methodology: Healthy women between 45-65 years old were enrolled between November 2018 and December 2019 at a private tertiary hospital in Malaysia. Women were randomly assigned into the 100mg/day ISF Supplement arm, 50mg/day ISF Diet arm, or Control arm. Dense area was assessed from digital mammograms conducted at enrolment and after 12 months. We compared absolute and relative change in dense area over the study period by study arm using Kruskal Wallis tests. Results: Of the 118 women who received the intervention, 91 women completed the study whilst 27 women (23%) were lost to follow up. After 12 months of intervention, women in the ISF Supplement arm observed a marginally larger decline in dense area (-1.3cm2), compared to women in the ISF Diet arm (-0.5cm2) and Control arm (-0.8cm2), but this difference was not statistically significant (p=0.479). Notably, these effects appear to be stronger and limited to women who enrolled within 5 years of menopause, where up to 6cm2 decline in MD was observed in the ISF Supplement arm, compared to < 1.0cm in the Control arm (p=0.131). Conclusion: This RCT demonstrates a possible causal association between soy ISF intake and lower breast cancer risk among Asian women, specifically around the time of menopause, but these findings will require confirmation in a larger trial.

Citation Format: Nadia Rajaram, Beverley Yap, Mikael Eriksson, Shivaani Mariapun, Lee Mei Tan, Hamizah Saat, Evelyn Ho, Nur Aishah Mohd Taib, Geok Lin Khor, Cheng Har Yip, Weang Kee Ho, Per Hall, Soo Hwang Teo. A randomized controlled trial of soy isoflavone intake on mammographic density among Malaysian 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 P2-06-02.
Abstract P2-11-01: Secondary endocrine resistance and high Ki-67 labeling index (≥20%) in patients with low genomic risk identified by 21-gene recurrence score
Authors: Lee Janghee , Kim Hakyoung , Bae Soong June , Lee Jong Won , Son Byung Ho , Ahn Sei Hyun , Jeong Joon , Lee Sae Byul , Ahn Sung Gwe
Published: March 2023

Introduction: Although breast cancer with high Ki-67 index are likely to have high genomic risk, some of these might have low genomic risk. In ER+HER2- breast cancer patients with low genomic risk identified by the 21-gene assay, we addressed a clinical significance of Ki-67 index in terms of recurrence-free survival (RFS). Methods: We retrospectively identified 2,295 patients with ER+HER2- breast cancer who underwent the 21-gene assay (Oncotype DX®). High Ki-67 LI was defined as 20% or greater, and low genomic risk was defined by recurrence score (RS) from the assay (< 26). Recurrence after 3 year was regarded as secondary endocrine resistance, which is defined as recurrence while on 2 years of adjuvant endocrine treatment. Results: In all patients, Ki67 index assigned 870 (38%) as the high and 1,425 (62%) as the low groups. Thirty percent (263/870) of the high Ki67 index had high genomic risk, whereas 84/1425 (6%) of the low Ki67 did. Among the patients with low genomic risk who did not receive chemotherapy (n=1,807), high Ki67 index was an independent poor risk factor for recurrence. Furthermore, recurrence after 3 years differed significantly according to Ki-67 index (P=0.003), whereas recurrence within 3 years did not differ (P=0.900). Multivariable analysis demonstrated high Ki67 index as a risk factor for recurrence after 3 years (hazard ratio 3.12; 95% confidence interval, 1.28–7.66). Conclusions: In ER+HER2- breast cancer with low genomic risk identified by 21-gene RS, high Ki67 index is associated with secondary endocrine resistance. Novel approach with CDK4/6 inhibitors is demanded to overcome secondary endocrine resistance in tumors with high Ki67/low genomic profile.

Citation Format: Janghee Lee, Hakyoung Kim, Soong June Bae, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Joon Jeong, Sae Byul Lee, Sung Gwe Ahn. Secondary endocrine resistance and high Ki-67 labeling index (≥20%) in patients with low genomic risk identified by 21-gene recurrence score [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-01.
Abstract P2-11-02: BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET)
Authors: Murillo Serafin Morales , Cudós Ariadna Gasol , Der-Abrain Noemí Tuset , Urdanibia Izaskun , Galindo Alvaro Rodriguez , Sánchez Ana Velasco , Villellas Felip Vilardell , Guzmán Douglas Sánchez , Morales Carles Canosa , Olivé Jordi Melé , Cid Laura Arbones
Published: March 2023

Treatment with CDK4/6i plus ET is the standard treatment for mBC with a significantly better progression free survival (PFS) and a long treatment duration response, although there’s finally a progression. The expression of cyclin E and progesterone receptor had been related to survival, so analyzing of these potential biomarkers could help to select their effect in patients with a long treatment duration (> 20 months). We evaluate 68 mBC treated with CDK4/6I plus ET as a clinical practice in a single institution. Median age was 68 years, 27(39,7%) patients had de novo metastatic disease, 17 (25%) progressed during ET adjuvant, and 24 (35,3%) progressed after 5 years of ET. Forty-eight patients (70%) received CDK4/6I plus ET in first line and visceral disease was present in 40% of patients. The median expression by histoscore with immunohistochemistry of cyclin E (CycE) was 75,3 (4-97) and progesterone receptor (PR) 121. Median PFS was 16 months (8,3- 23,6) with 45 events, 25 months in patients treated in first line and 12 months in second line (p: 0,0001). We analyzed 59 patients who had already completed CDK4/6I plus ET or had achieved a PFS more than 20 months, 40 (69%) in first line and 18 (31%) in second line. We summarized the related of expression of PR, CycE and this combination with PFS more than 20 month.

CONCLUSION: Treatment with CDK4/6i plus ET achieved long treatment duration in patients with low expression of cyclin E (OR 3,1 p:0,045), positive progesterone receptor (OR 3,89 p: 0023) and specially in patients with positive progesterone receptor and low expression of cyclin E (OR 7,22 p:0,016). Patients with negative progesterone receptor and high expression of cyclin E had a poor prognosis with a median disease-free survival of 6 months (2.8 – 9.2), so these patients required other treatment approaches to improve their outcomes.

Table

Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain, Izaskun Urdanibia, Alvaro Rodriguez Galindo, Ana Velasco Sánchez, Felip Vilardell Villellas, Douglas Sánchez Guzmán, Carles Canosa Morales, Jordi Melé Olivé, Laura Arbones Cid. BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-02.
Abstract P2-11-21: Outcomes and Treatment Pattern in Women With 1 cm or Smaller, Node-Negative Hormone Receptor-negative Breast Cancer in Fudan University Shanghai Cancer Center
Authors: Liu Xiyu , He Min
Published: March 2023

Background: To evaluate the outcome the treatment pattern in women diagnosed with T1mic, T1a and T1b, node-negative, hormone receptor (HR) –negative breast cancer.

Methods: This was a retrospective cohort study within the Fudan University Shanghai Cancer Center (FUSCC) that included 605 women with T1mic,a,bN0M0 breast cancer treated between 2010 and 2020. Tumors were grouped by size (T1mic, T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. Kaplan-Meier product was used to calculate invasive disease-free survival (iDFS), breast cancer-specific survival (BCSS) and overall survival (OS).

Results: Median follow-up time was 5.0 years. Seventy-three percent of patients with triple-negative breast cancer (TNBC) were treated with chemotherapy. For those with HER2- positive breast cancers, 82% received chemotherapy, and 71% received trastuzumab. The treatment pattern varied over the years, with a downward trend of chemotherapy in TNBC and an upward trend of trastuzumab in HER2-positive breast cancer. Survival outcomes diverged by subtype and size. In this retrospective cohort study, the 5-year DFS for treated patients with T1mic,a tumors ranged from 96.2% to 97.7%, and for patients with T1b tumors, it ranged from 92.1% to 95.0%. The 5-year DFS for patients with T1mic,a tumors untreated with chemotherapy or trastuzumab was 100%. The 5-year DFS for TNBC patients with T1b tumors untreated with chemotherapy was 90.5%, while for HER2-positive patients with T1b tumors untreated with chemotherapy or trastuzumab it was 87.5%,

Conclusion: Women with T1mic,a tumors have an excellent prognosis without chemotherapy or trastuzumab, representing an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks.

Figure 1 Systematic Treatment Pattern of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer from 2010 to 2020 Figure 1 Systematic Treatment Pattern of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer from 2010 to 2020

Table 1. Patient Demographics and Clinicopathologic Characteristics for T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer, FUSCC 2010-2020

Table 2 Systematic Treatment of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer, FUSCC 2010-2020

Citation Format: Xiyu Liu, Min He. Outcomes and Treatment Pattern in Women With 1 cm or Smaller, Node-Negative Hormone Receptor-negative Breast Cancer in Fudan University Shanghai Cancer Center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-21.
Abstract P2-14-19: Targeted Axillary Lymph Node Dissections Using Radar Reflector Localization Can Reduce Unnecessary Axillary Lymph Node Dissections in Node Positive Patients Treated with Neoadjuvant Chemotherapy
Authors: Lunt Lilia , Coogan Alison , Madrigrano Andrea , O’Donoghue Cristina
Published: March 2023

Background Targeted axillary dissection (TAD) is a surgical strategy that involves staging the axilla through sentinel lymph node biopsy (SLNB) combined with the removal of a biopsy-proven positive lymph node identified by a clip. TAD reduces the false negative rate of SLNB alone in patients with clinically detected nodal metastasis who receive neoadjuvant chemotherapy (NAC) while avoiding axillary lymph node dissections (ALND). Radar reflector-localization (RRL) can be used to identify previously positive nodes and safely and effectively guide dissection. Methods We performed an institutional retrospective chart review of breast cancer patients with clinical stage T1-3 and N1-3 disease treated with NAC from 2015 to 2020 who had a biopsy proven positive node and underwent TAD using RRL. The primary outcome was the retrieval of clipped node as documented by gross visualization or specimen radiography. Secondary outcomes included pathologic complete response rates and completion axillary lymph node dissections (cALND). Results 79 patients were identified who fulfilled inclusion criteria. 32 (40.5%) had RRL markers placed prior to chemotherapy (mean 187 days prior to surgery) and 47 (59.5%) had RRL markers placed following the completion of chemotherapy (mean 7 days prior to surgery). The clipped node was retrieved in 77 patients (97.5%). 32 of the 34 ypN0 (i+) patients avoided an ALND; 1 patient had a cALND for failure to localize the RRL and 1 patient had a cALND for a false-positive on frozen section. There was no significant difference in clip recovery rates in the pre vs post NAC RRL groups (p=1.00). Conclusion RRL systems are an effective way to guide TAD with a high success rate in identifying and removing previously biopsied nodes. These markers can be placed prior to NAC without migration or deactivation. This strategy allows surgeons to avoid unnecessary cALND.

Citation Format: Lilia Lunt, Alison Coogan, Andrea Madrigrano, Cristina O’Donoghue. Targeted Axillary Lymph Node Dissections Using Radar Reflector Localization Can Reduce Unnecessary Axillary Lymph Node Dissections in Node Positive Patients Treated with Neoadjuvant 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 P2-14-19.
Abstract P2-14-22: Evaluation of male breast cancer and the application of sentinel lymph node biopsy: A multi-center retrospective study
Authors: Shang Qingyao , Wei Ya , Qiao Guangdong , Li Jingruo , Wang Xin
Published: March 2023

Objective:Sentinel lymph node biopsy (SLNB) is currently used as a routine treatment for breast cancer patients. Many clinical studies, such as the NSABP B-32, have demonstrated that SLNB can safely replace axillary lymph node dissection (ALND) for patients with clinically node-negative breast cancer. However, it may not be applicable for male breast cancer (MBC) patients because they have notably different clinicopathological features from those occurring in females. There is a lack of evidence of SLNB application and safe exemption from ALND in MBC patients. This study aimed to evaluate the application of SLNB to provide information for the standardized treatment of MBC patients.

Methods:The MBC patient records from four institutions ranging from January 2001 to November 2020 were retrospectively reviewed. Patients undergoing surgery as a primary treatment were included. Patients with stage IV and non-primary breast cancer were excluded. Patients were followed up postoperatively for survival analysis. The primary outcome was disease-free survival (DFS), and the secondary outcome was overall survival (OS).

Results:There were 220 MBC patients with a median age of 60 (range 24-88) years and an average tumor size of 2.3 cm (range 0.5 cm - 6.5 cm). MBC patients were characterized by old age, advanced stage, and higher pathological grade. The median follow-up time was 5.0 (range, 1.0-17.3) years. Survival analysis showed the 5-year DFS and OS were 73.5% and 83.3%, respectively. 66 patients (30%) underwent SLNB and 39% of them showed positive results. 157 patients (71%) underwent ALND, while only half of them had positive nodes, causing unnecessary complications. For 92 patients at clinical early-stage (stage I or IIA), 28 patients only had SLNB as axillary treatment, 26 patients only had ALND and 38 patients underwent SLNB and ALND. From Kaplan-Meier survival analysis, we found that the SLNB showed a non-inferiority to the ALND treatment in DFS (p=0.18) and OS (p=0.055).

Conclusion:MBC patients are older at the time of diagnosis and present a higher pathological grade. There are certain obstacles to the broad application of SLNB due to the lower proportion of clinically-negative lymph node patients. However, it is undeniable that SLNB can safely and effectively exempt MBC patients at early-stage with clinically-negative nodes from ALND to reduce subsequent complications. It’s still an ideal criterion for the axillary staging of MBC patients.

Clinicopathologic characteristics of MBC patients

Citation Format: Qingyao Shang, Ya Wei, Guangdong Qiao, Jingruo Li, Xin Wang. Evaluation of male breast cancer and the application of sentinel lymph node biopsy: A multi-center retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-22.
Abstract P2-15-02: Omentum-Lipoaspirate Free-Flap Breast Reconstruction in Women with BMI <25
Authors: Wapnir Irene L. , Dua Monica M. , Zak Yulia , Nguyen Dung
Published: March 2023

The Omental Fat-Augmented Free-flap (O-FAFF) is being offered at our institution as an alternative method of breast reconstruction. This novel free-flap construct is ideal for underweight and normal weight women who lack abdominal or other donor tissue, desire to avoid donor site morbidity and/or are averse to implant-based reconstruction. We analyze omentum, mastectomy and final construct weights in women with BMI < 25 kg/m2 who underwent nipple-sparing mastectomies and O-FAFF reconstruction. Methods Operative technical features of women undergoing nipple-sparing mastectomies with immediate O-FAFF breast reconstruction over a 34 month period are included. Steps of the operative procedure are as follows: laparascopic omentectomy, liposuction and unilateral or bilateral mastectomy is performed. An acellular dermal matrix (ADM) shell is fashioned around a tissue expander. This mold is filled with the omentum and then engrafted with lipoaspirate followed by microsurgical anastomoses of gastroepiploic artery and vein to internal mammary artery and vein. Weight of biological construct is compared to native breast weight. Results 26 women with average BMI 21.2 kg/m2 underwent unilateral (15) or bilateral (11) nipple-sparing mastectomies and O-FAFF reconstruction. Average omentum weight for 37 breasts was 149 gm (82- 262) and average mastectomy weighed 212.4 gm (85 – 396). The ratio of engrafted fat to omentum weight was 0.73 for unilateral versus 0.91 for bilateral cases. The ratio of omentum-fat graft construct to mastectomy weight was 1.24 for unilateral and 0.96 for bilateral cases. Conclusion O-FAFF is a novel procedure for autologous tissue breast reconstruction after nipple-sparing mastectomy in underweight and normal weight women. Comparable weight replacement for extirpated native breast is achieved.

Citation Format: Irene L. Wapnir, Monica M. Dua, Yulia Zak, Dung Nguyen. Omentum-Lipoaspirate Free-Flap Breast Reconstruction in Women with BMI <25 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-15-02.
Abstract P2-22-02: The role of circular RNAs in triple-negative breast cancer and chemotherapy resistance
Authors: Wang Xiyin , Emch Michael , Hawse John
Published: March 2023

Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype representing 15-20% of all breast cancers. TNBC often ends with a poor clinical outcome due to high histological grade and recurrence rates with few treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance, and alternative treatment strategies for the chemoresistant disease remain a major unmet need. circRNAs are newly identified non-coding RNA molecules with covalently closed circular structures. Recently, an increasing number of studies have indicated that circRNAs play crucial roles in regulating tumor development and chemoresistance. However, the role of circRNAs in the process of TNBC chemotherapy resistance is not yet fully clear. Materials and methods: To study the molecular functions of circRNAs in TNBC chemoresistance, identify alternative biomarkers for chemotherapy-resistant disease, and elucidate novel therapeutic targets, doxorubicin-resistant (Doxo-R) and paclitaxel-resistant (Taxol-R) cell lines were generated using TNBC models. Results: Doxo-R and Taxol-R cells exhibited a 3- and 12-fold decrease in sensitivity to their respective chemotherapeutic agents. We identified a large spectrum of gene expression changes that were acquired in Doxo-R and Taxol-R cells. The expression of circRNAs was profiled using circRNA microarrays, and top hits were validated using RT-PCR. We identified 429 and 310 circRNAs that were differentially expressed in Doxo-R and Taxol-R resistant cells respectively compared to the parental chemosensitive cell line (|FC| ≥ 1.5; p value < 0.05). Of these, 66 were commonly differentially expressed between the two chemotherapy resistant models. Conclusions: These results revealed that Doxo-R and Taxol-R TNBC cell lines were successfully established and serve as good models for studying the mechanisms of chemotherapy resistance and the regulatory roles of circRNAs in the development of chemoresistance in TNBC. Increasing knowledge of the important functions of circRNAs underlying drug resistance will provide new opportunities for developing efficacious therapeutic strategies and prognostic/predictive biomarkers for TNBC.

Citation Format: Xiyin Wang, Michael Emch, John Hawse. The role of circular RNAs in triple-negative breast cancer and chemotherapy resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-22-02.
Abstract P3-01-01: Unicentric experience with icdk4/6 in metastatic breast cancer
Authors: Henao Fernando , Fernández Esteban Nogales , Ortega Lourdes Sevilla , Salas Ruben De Toro , Carrión Natalia Palazón , de la Gala Maria del Carmen Álamo , Mejías Alberto Sanchez-Camacho , Leon Maria Luisa Sanchez , de la Cruz-Merino Luis
Published: March 2023

Currently, the standard of care for luminal metastatic breast cancer is the combination of cyclin inhibitors with hormone therapy. Palbociclib and Ribociclib have been approved for marketing since 2017 and Abemaciclib since 2019 in Spain. In our center we have experience with the three cdk 4/6 inhibitors in different lines of treatment and patient profiles. We gather in the present work the unicentric experience with the three icdk 4/6. We have collected a total of 152 patients treated with the different cyclin inhibitors, achieving median PFS of 32.1 months for Palbociclib, 28.6 months for Ribociclib and 18.4 months for Abemaciclib. Overall survival data is still immature. The context of the patient and the disease has a significant impact on the results, as well as the line of treatment used. The toxicity profile of the three drugs does not differ from what the registry trials describe, with neutropenia being the most common side effect. We also describe dose reductions produced by the three icdk4/6. Conclusions: This is a real-life study with experience in a single center with the three icdk4/6 currently marketed with a cohort of more than 150 patients. We present data that conform to what was reported by the clinical trials PALOMA, MONALEESA and MONARCH. The data will be updated on the date of the congress for its presentation.

Citation Format: Fernando Henao, Esteban Nogales Fernández, Lourdes Sevilla Ortega, Ruben De Toro Salas, Natalia Palazón Carrión, Maria del Carmen Álamo de la Gala, Alberto Sanchez-Camacho Mejías, Maria Luisa Sanchez Leon, Luis de la Cruz-Merino. Unicentric experience with icdk4/6 in metastatic 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 P3-01-01.
Abstract P3-01-10: Going beyond the median: Estimating survival times for patients with hormone receptor positive, metastatic breast cancer commencing endocrine therapy
Authors: Parsonson Andrew O. , Sarkar Sunit , Brown Lauren , Kiely Belinda , Vasista Anuradha
Published: March 2023

Background: Oncologists are often asked to provide information about expected survival times for patients with metastatic breast cancer (MBC). We have previously demonstrated that using estimates of best-case, typical and worst-case scenarios for survival to explain life expectancy conveys more meaning and hope than simply providing single point estimates of the median overall survival (OS). Our aim was to assess whether using simple multiples of the median could accurately assess scenarios for survival for patients with estrogen receptor (ER) positive, MBC starting endocrine therapy (ET) using simple multiples of the median. Methods: We systematically searched for randomised trials of ET for ER positive MBC. We then recorded the following percentiles (representative scenarios) from the OS curve of each trial using UN-SCAN-IT® graph digitising software: 90th (worst-case), 75th (lower-typical), 50th (median) 25th (upper-typical), and 10th (best-case). We assessed the accuracy of estimating these percentiles for each OS curve by multiplying the median OS by four simple multiples: 0.25 (to estimate the 90th percentile), 0.5 (75th), 2 (25th) and 3 (10th). Estimates were deemed accurate if within 0.75 -1.33 times the actual value. Results: We identified 24 trials with 10,068 patients. The median OS (interquartile range [IQR]) was: 61.3 months (53.4-64.8) for first-line ET with cyclin-dependant kinase 4/6 inhibitors (CDK4/6i) (4 treatment groups); 42.6 months (40.9-50.4) for first-line ET alone (23 treatment groups) and 29.2 months (24.8-33.4) for subsequent line ET (21 treatment groups). The median OS (IQR) for each scenario for first-line ET with CDK4/6i was: worst-case 17.4 months (13.8-20.7); lower-typical 32.5 months (29.3-34.9); upper-typical and best-case percentiles were not available. Simple multiples of the median OS accurately estimated the 90th percentile in 79%; 75th percentile in 93%; and 25th percentile in 76% of curves. The 10th percentile was only available for four OS curves and could not be accurately assessed. Conclusion: Using simple multiples of the median OS to estimate and explain survival times to patients with MBC starting ET, is accurate and meaningful. Longer follow-up of trials is required to help clinician’s estimate the best-case scenario for these patients.

Citation Format: Andrew O. Parsonson, Sunit Sarkar, Lauren Brown, Belinda Kiely, Anuradha Vasista. Going beyond the median: Estimating survival times for patients with hormone receptor positive, metastatic breast cancer commencing endocrine therapy [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 P3-01-10.
Abstract P3-03-23: Breast Cancer and Subsequent Risk of Type 2 Diabetes Mellitus: A systematic review and Meta-Analysis
Authors: Jordt Nanna , Kjærgaard Kasper , Borgquist Signe , Thomsen Reimar W. , Cronin-Fenton Deirdre
Published: March 2023

Introduction Due to improvements in breast cancer (BC) diagnostics and treatment, the population of BC survivors is growing. BC treatments may have adverse effects that lead to an increased risk of developing type 2 diabetes mellitus (T2D). It is therefore important to investigate the risk of T2D in patients with BC in general and according to type of adjuvant BC treatment. Objectives To conduct a systematic review and meta-analysis investigating the association between early BC and the risk of subsequent T2D diagnosis. A secondary aim was to examine this association according to type of adjuvant BC treatment––chemotherapy and endocrine therapy (ET). Methods We searched PubMed and Embase using variations of the search terms breast cancer (population), ET, tamoxifen, aromatase inhibitors (AIs) and chemotherapy (exposures), and diabetes mellitus (outcome). Two authors screened papers for eligibility by title and abstract using Covidence and reviewed full texts of eligible papers. Guided by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist, study data were extracted. Using random-effects models, we calculated relative risks (RRs) and associated 95% confidence intervals (CIs) for the association between BC, adjuvant BC treatment (ET overall, tamoxifen, and AIs), and subsequent T2D. We used funnel plots to assess publication bias in the analyses. Results Among 16 eligible studies, 11 reported on T2D risk after BC, chemotherapy, or ET; five studies investigated more than one association. Compared with patients without BC, those with BC had elevated risk of T2D overall (RR=1.27, 95%CI=1.15-1.41), particularly those who received any ET (RR=1.23, 95% CI=1.16-1.32). Among BC patients only, risk of T2D was higher for those who received tamoxifen compared with those who did not receive tamoxifen (RR=1.19, 95% CI=1.13-1.25). Due to few studies, analyses investigating T2D risk after treatment with AIs and chemotherapy were inconclusive. Conclusion Our findings support an association between BC and subsequently elevated risk of T2D, particularly after tamoxifen use. Further research is needed to determine the impact of ET overall, AIs and chemotherapy on the incidence of T2D in patients with early BC. Funding This project was funded from the following source: The Novo Nordisk Foundation (NNF20OC0065928)

Citation Format: Nanna Jordt, Kasper Kjærgaard, Signe Borgquist, Reimar W. Thomsen, Deirdre Cronin-Fenton. Breast Cancer and Subsequent Risk of Type 2 Diabetes Mellitus: A systematic 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 P3-03-23.
Abstract P3-05-11: Breast cancer characteristics in premenopausal women by contraception method
Authors: De Maeyer Inés , Borowski Eline , Van Baelen Karen , Laenen Annouschka , Nevelsteen Ines , Wildiers Hans , Han Sileny , Smeets Ann , Baert Thaïs , Punie Kevin , Neven Patrick
Published: March 2023

INTRODUCTION: Our knowledge regarding the levonorgestrel intra-uterine device (LNG-IUD) and breast cancer (BC) risk is limited. As the LNG-IUD is a widely used contraception method, we here explored receptor expression in BC, in women < 56 years, by having a LNG-IUD at diagnosis. We aim to validate the findings of a previous cohort treated in the University Hospitals Leuven, where we observed proportionally more progesterone receptor (PR), lower human epidermal growth factor receptor 2 (HER2) expression and more ER+PR+HER2- subtypes in LNG-IUD users compared to non-LNG-IUD users. MATERIALS AND METHODS: We conducted a retrospective observational monocentric study from 2015 until 2020. We included patients < 56 years consulting the University Hospitals Leuven for primary invasive BC, who were treated with primary breast surgery or neoadjuvant therapy. We compared patient and tumor characteristics, especially receptor subtypes in LNG-IUD users at diagnosis with non- LNG-IUD users. Group comparisons with regards to receptor subtypes were performed by the Chi-square test, all tests were evaluated at a two-sided 5% significance level. RESULTS: Of the 1347 patients with BC included in this study, 272 had a LNG-IUD at diagnosis. The LNG-IUD users were more likely ER (85.29% vs 77.77%, p=0.006) and PR positive (80.88% vs 70.95%, p< 0.001) compared to the control group. Additionally, we observed more ER+PR+HER2- (68.75% vs 58.62%, p=0.002) and fewer ER-PR- HER2- (10.29% vs 15.66%, p=0.025) subtypes when comparing with the control group. CONCLUSION: This internal validation study confirmed invasive BC, diagnosed in women under age 56, to be more likely PR+ and ER+PR+HER2- if they used a LNG- IUD at BC diagnosis when compared to non-LNG-IUD users.

Citation Format: Inés De Maeyer, Eline Borowski, Karen Van Baelen, Annouschka Laenen, Ines Nevelsteen, Hans Wildiers, Sileny Han, Ann Smeets, Thaïs Baert, Kevin Punie, Patrick Neven. Breast cancer characteristics in premenopausal women by contraception method [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 P3-05-11.
Abstract P3-05-37: Influence of Clinical Heterogeneity on Pregnancy Associated Breast Cancer survival: Systematic Review with Metanalysis
Authors: ANTONINI MARCELO , TAIS BARROS T. , REAL JULIANA M. , LOPES REGINALDO G. COELHO , FERRARO ODAIR , MATTAR ANDRE , OKUMURA LUCAS
Published: March 2023

Objective: Pregnancy-associated breast cancer (PABC) is defined as diagnosed during pregnancy or within one year of childbirth, in which current evidence associates with poor prognosis, without showing what clinical characteristics could impact in survival. We aim to explore the impact of heterogeneity in risks on death and disease relapse, suggesting clinical characteristics that might improve PABC clinical outcomes.

Methods: Medline, Embase, Cochrane, Lilacs and congress abstracts published since 2000 were used as data sources. Two reviewers independently selected manuscripts and extracted data and a third reviewer solved discrepancies. The primary outcome was overall survival (death), and secondary outcome was disease-free survival (death or relapse). Summarized hazard ratios were recalculated based on reported data. All metaanalyses used a random-effects model and heterogeneity was reported using the I2 method.

Results: A total of 7143 studies were identified and 30 studies were included for metaanalyses. PABC is associated with a 96% (HR=1.96, 95%CI 1.58;2.35) higher risk of death and an additional 82% (HR=1.82, 95%CI 1.45;2.20) risk of death or disease relapse in comparison to a population of non-PABC or nulliparous BC. Through sensitivity analyses, we identified that clinical outcomes was impacted, possibly due to Ki-67 levels, poorly differentiated tumors, and triple negative breast cancer (TNBC) frequency in the study.

Conclusions: PABC is correlated with poorer prognosis, suggesting that besides early diagnosis, Ki-67 levels, poorly differentiated tumors and TNBC might be relevant sources of inconsistency. So, such clinical sources of heterogeneity should be better investigated regarding the potential to evaluate alternative therapeutic strategies.

PABC deaths compared to non-PABC population, represented as hazard ratio

PABC deaths or disease relapse compared to non-PABC population, represented as hazard ratio

Citation Format: MARCELO ANTONINI, BARROS T. TAIS, JULIANA M. REAL, REGINALDO G. COELHO LOPES, ODAIR FERRARO, ANDRE MATTAR, LUCAS OKUMURA. Influence of Clinical Heterogeneity on Pregnancy Associated Breast Cancer survival: Systematic Review with Metanalysis [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 P3-05-37.
Abstract P3-05-50: Comprehensive Analysis of Pyroptotic Gene Prognostic Signatures Associated with Tumor Immune Microenvironment and Genomic Mutation in Breast Cancer
Authors: Zhang Hongfei , Yu Xiafei , Yang Junzhe , Liu Xiaoan , Zhu Yanhui
Published: March 2023

Background: Breast cancer is becoming a tumor with the highest morbidity rate, and inflammation-induced cell death namely pyroptosis reportedly plays dual roles in cancers. However, the specific mechanism between pyroptosis and the clinical prognosis of breast cancer patients is indistinct. Hence, novel pyroptosis-related biomarkers and their contributing factors deserve further exploration to predict the prognosis in breast cancer. Methods: Pearson’s correlation analysis, and univariate and multivariate Cox regression analysis were utilized to obtain six optimal pyroptosis-related gene prognostic signatures (Pyro-GPS). The risk score of each breast cancer patient was calculated. Next, a Pyro-GPS risk model was constructed and verified in TCGA cohort (n=1,089) and GSE20711 cohort (n=88). Then analyses of immune microenvironment, genomic variation, functional enrichment, drug response and clinicopathologic feature stratification associated with the risk score of Pyro-GPS were performed. Ultimately, a nomogram based on the risk score and several significant clinicopathologic features was established. Results: The low-risk breast cancer patients have better survival outcomes than the high-risk patients. The low-risk patients also show higher immune cell infiltration levels and immune-oncology target expression levels. There is no significant difference in genetic variation between the two risk groups, but the frequency of gene mutations varies. Functional enrichment analysis shows that the low-risk patients are prominently correlated with immune-related pathways, whereas the high-risk patients are enriched in cell cycle, ubiquitination, mismatch repair, homologous recombination and biosynthesis-related pathways. Pyro-GPS is positively correlated with the IC50 of anti-tumor drugs. Furthermore, comprehensive analyses based on risk score and clinicopathological features were performed to predict the prognosis of breast cancer patients. Conclusions: The risk score of Pyro-GPS can serve as a promising hallmark to predict the prognosis of BRCA patients. Risk score evaluation may assist to acquire relevant information of tumor immune microenvironment, genomic mutation status, functional pathways and drug sensitivity, and thus provide more effective personalized strategies.

Citation Format: Hongfei Zhang, Xiafei Yu, Junzhe Yang, Xiaoan Liu, Yanhui Zhu. Comprehensive Analysis of Pyroptotic Gene Prognostic Signatures Associated with Tumor Immune Microenvironment and Genomic Mutation in 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 P3-05-50.