tbuckley/cabot-search huggingface dataset:
Abstract PO4-23-08: Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer
Authors: Nicole Traphagen, Gary Schwartz, Steven Tau, Alyssa Roberts, Amanda Jiang, Sarah Hosford, Jonathan Marotti, Abigail Goen, Bianca Romo, Anneka Johnson, Emily Duffy, Eugene Demidenko, Paul Heverly, Yaron Mosesson, Shannon Soucy, Fred Kolling, Todd Miller
Journal: Cancer Research (2024)

Abstract Although clinical evidence indicates that treatment with estrogens elicits anti-cancer effects in ~30% of patients with advanced endocrine-resistant ER+ breast cancer, the underlying mechanism of action is unclear and this treatment remains under-utilized. ER+ breast cancer cells with acquired resistance to long-term estrogen deprivation (LTED) were used to model resistance to aromatase inhibitors (AIs) seen clinically. Genome-wide CRISPR/Cas9 knockout screening and transcriptomic profiling of LTED cells highlighted DNA Damage Response as a required pathway for therapeutic response to the estrogen 17b-estradiol. Tumor specimens from 2 patients with advanced ER+ breast cancer showed increased DNA damage response upon treatment with 17b-estradiol therapy compared to baseline. LTED cells treated with 17b-estradiol exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis, while parental cells did not. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops), and RNase H1-mediated prevention of R-loop formation abrogated 17b-estradiol-induced DNA damage. Pharmacological suppression of the DNA damage response via poly(ADP-ribose) polymerase (PARP) inhibition with olaparib enhanced 17b-estradiol-induced DNA damage. PARP inhibition synergized with 17b-estradiol to suppress growth and prevent tumor recurrence in both BRCA1/2-mutant and BRCA1/2-wild-type cell line and patient-derived xenograft models. We therefore conclude that 17b-estradiol-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells, and inhibition of the DNA damage response using drugs such as PARP inhibitors can exacerbate transcriptional stress and enhance therapeutic response to 17b-estradiol. This concept is being explored clinically in the PHOEBE trial testing the combination of 17b-estradiol and olaparib (NCT05900895). These findings also warrant further study of other DNA damage response inhibitors in advanced ER+ breast cancer. Moreover, these data indicate that PARP inhibitors may have applications beyond homologous recombination-deficient tumors. Citation Format: Nicole Traphagen, Gary Schwartz, Steven Tau, Alyssa Roberts, Amanda Jiang, Sarah Hosford, Jonathan Marotti, Abigail Goen, Bianca Romo, Anneka Johnson, Emily Duffy, Eugene Demidenko, Paul Heverly, Yaron Mosesson, Shannon Soucy, Fred Kolling, Todd Miller. Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-08.
Abstract PO5-21-01: Carcinoma en cuirasse- a rare, but striking, cutaneous manifestation of metastatic breast cancer
Authors: Manasi Godbole, Kashmira Wani, Shereen Zia, Vrushali Dabak
Journal: Cancer Research (2024)

Abstract Introduction: Carcinoma en cuirasse is a rare cutaneous metastatic presentation most commonly arising from primary breast cancers, typically after mastectomy. It appears like cellulitis and later develops into thickened rough patches of skin and even nodules. Carcinoma en cuirasse holds a poor prognosis, and treatment is difficult. Chemotherapeutic agents are unable to reach the tumor cells necessary, and radiation is ineffective because of skin curvature. Case Presentation: We report a female in her 70s with prior history of left breast ductal carcinoma in situ status post-radiation and lumpectomy, who presented with skin thickening of the left breast and solid masses in bilateral breasts 10 years later. Biopsy showed invasive ductal carcinoma of left breast (estrogen receptor [ER]/progesterone receptor positive [PR], human epidermal growth factor receptor-2 [HER2] negative) and ductal carcinoma in situ of right breast (ER/PR positive). She underwent right breast lumpectomy; however, the left breast mastectomy was aborted due to worsening of her skin findings on preoperative examination. An excisional skin biopsy revealed poorly differentiated invasive ductal carcinoma involving the dermis, deep dermis and focally involving the epidermis. Her diagnosis changed to stage 4 breast cancer, specifically carcinoma en cuirasse. Systemic treatment was initiated with palbociclib and letrozole and subsequently, she underwent left breast mastectomy given an excellent response to initial therapy. Surgical biopsy interestingly was HER2 positive and therefore her regimen was changed to taxotere, trastuzumab and pertuzumab. She completed adjuvant treatment and has been on maintenance trastuzumab along with letrozole currently and is doing well 5 years later with negative PET scans. Discussion: Our case is unique due to diagnosis of carcinoma en cuirasse before mastectomy, change in HER2 receptor status during treatment and excellent response to therapy with ongoing response to date. We think that an early diagnosis as well as targeted treatment could be the possible reasons for prolonged survival of more than 5 years. Conclusion: Any unexplained skin findings in breast cancer patients should prompt consideration of carcinoma en cuirasse. With ongoing treatment advances, many newer therapy options are available for metastatic breast cancer. Based on our case, we think that patients with this disease can have better outcomes. Citation Format: Manasi Godbole, Kashmira Wani, Shereen Zia, Vrushali Dabak. Carcinoma en cuirasse- a rare, but striking, cutaneous manifestation of metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-01.
Abstract Wrk2-04: Virtual screening of ultra-large chemical spaces for novel chemotype discovery
Authors: J. Irwin
Journal: Cancer Research (2024)

Abstract Recently, 'tangible' virtual libraries have made billions of molecules readily available. Prioritizing these molecules for synthesis and testing demands computational approaches, such as docking. We will present recent results in which protein structure is interrogated using molecular docking, resulting in new high-affinity compounds that exhibit new biology in animal models. Singh I, Seth A, Billesbølle CB, Braz J, Rodriguiz RM, Roy K, Bekele B, Craik V, Huang XP, Boytsov D, Pogorelov VM, Lak P, O'Donnell H, Sandtner W, Irwin JJ, Roth BL, Basbaum AI, Wetsel WC, Manglik A, Shoichet BK, Rudnick G. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell. 2023 May 11;186(10):2160-2175.e17. doi: 10.1016/j.cell.2023.04.010. Epub 2023 May 2. PMID: 37137306; PMCID: PMC10306110. Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 Sep 30. PMID: 36173843; PMCID: PMC10360211. Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. 2022 Oct;610(7932):582-591. doi: 10.1038/s41586-022-05258-z. Epub 2022 Sep 28. PMID: 36171289; PMCID: PMC9996387. Citation Format: J. Irwin. Virtual screening of ultra-large chemical spaces for novel chemotype discovery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Wrk2-04.
Abstract PO4-22-06: Outcomes following Stereotactic Radiotherapy in Oligometastatic Breast Cancer: a single centre retrospective review
Authors: Sophie Lynch, Sugeeta Sukumar, Elinor Sawyer, Daniel Smith, Christy Goldsmith
Journal: Cancer Research (2024)

Abstract Introduction: Stereotactic radiotherapy (SABR) is an increasingly used treatment for oligometastatic disease with evidence of survival benefit shown in the SABR-COMET trial. However, the benefit in oligometastatic breast cancer has been brought into question following initial results from the NRG-BR002 trial. Methods: A retrospective review of all patients with primary breast cancer treated with stereotactic radiotherapy for oligometastases at our institution was carried out. A total of 31 patients received treatment to 36 lesions between August 2015 and December 2022. Results: Neither median overall survival nor progression free survival were reached after median follow up time of 21.5 months. Hormone receptor status as follows: ER+, HER2- (n=25), ER+, HER2+ (n=4,), TNBC (n=2). The majority of lesions treated were bony metastases (92%, of which 17 vertebral and 11 pelvic lesions). The majority had oligometastatic disease at time of SABR (67%), with 33% treated for oligoprogression. Most patients were on systemic anti-cancer therapy (SACT) at the time of SABR, or had a planned start of SACT shortly following treatment. Breakdown of systemic therapy as follows: Endocrine therapy (ET) alone 9 patients (29%), CDK4/6 inhibitor plus ET 13 patients (42%), chemotherapy 3 patients (10%), antibody drug conjugate 2 (6%), anti-HER2 therapy + ET 2 patients (6%), none 2 patients (6%). All patients also received bone-targeted agents (zoledronic acid or denosumab). Local control was achieved in 33 lesions (92%), all of which were bony lesions. Local control was maintained in both patients who were not on SACT: one patient with ER+ HER2- disease developed distant progression after 27 months, the other with TNBC remains disease free after 13 months. Loss of local control was observed in all non-bony sites (lung, IMC node, peri-ureteric soft tissue mass) at a median interval of 10 months (range 7-43 months). 14 patients subsequently developed distant disease progression at median interval of 15 months (range 0-43 months). 12 month progression free survival was 77%. 13 patients received further SACT at median interval of 16 months. Conclusions: SABR for bony metastases from breast cancer has excellent local control rates in combination with systemic treatment but may also give patients significant time off treatment. Questions remain regarding the ideal sequencing and combination of SABR and SACT, particularly in hormone receptor positive patients where there are a number of lines of effective SACT. Citation Format: Sophie Lynch, Sugeeta Sukumar, Elinor Sawyer, Daniel Smith, Christy Goldsmith. Outcomes following Stereotactic Radiotherapy in Oligometastatic Breast Cancer: a single centre retrospective review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-06.
Abstract PO5-10-11: BREAST CANCER DIAGNOSIS AND TREATMENT AMONG DISPLACED AND HOST POPULATIONS IN NORTH-WEST SYRIA
Authors: Anees Chagpar, Aula Abbara, Alaa Alshemali, Fares Alahdab, Moahmed Hamze, Bassel Attassi, Jude Alawa, Sydney Cech, Lawrence Tang, Kaveh Khoshnood
Journal: Cancer Research (2024)

Abstract INTRODUCTION: The protracted Syrian conflict has forcibly displaced more than half the pre-conflict population of 22 million people with 6.7 million IDPs (internally displaced people.) 80% of IDPs are women and children. Given a lack of humanitarian funding for oncology services, NGOs like the Syrian-American Medical Society (SAMS), have used private funding to establish oncology services. We sought to explore differences in breast cancer diagnosis and treatment among IDPs and host populations in SAMS oncology centre in Idlib governorate. METHODS: Charts of women seen diagnosed with breast cancer at the SAMS Oncology Centre in Idlib governorate between March 2018 and February 2021 were reviewed. Clinicopathologic data was extracted, and non-parametric statistical analyses were performed to compare citizens vs. those who were displaced. RESULTS: Data for 188 patients were available; for 108/188 (57%) details of IDP versus host status was available. 61/108 (56%) were IDPs, 47 (44%) were host. The median age at diagnosis was similar between citizens and those who were displaced. Further, the clinicopathologic features and treatment between these two groups were similar. The time between onset of symptoms and diagnosis was imilar between the host population and IDPs (median 125.5 days vs. 77 days, respectfully, p=0.255), although there was a trend towards a shorter time from diagnosis to initiation of treatment for IDPs (median 19 days vs. 14 days, p=0.051). CONCLUSION: From this cohort study, it is notable that there were no significant differences in the tumor size, node positivity or grade at diagnosis. Further, although IDPs are usually considered to have more challenging access to healthcare services compared to host populations, it was notable that there was no significant difference between the time of onset of symptoms to diagnosis between the two groups, and a trend towards a shorter time to treatment. Although this may be related to the relatively small sample size, it may also reflect other commitments of host populations (e.g., employment) that may delay care, or the work of humanitarian organizations in reaching displaced populations. Further, given that in northwest Syria, more than 65% of the 4-4.6 million people in the area are IDPs, access to care between the two groups may be similar. Further work is required to explore this. Table. Citation Format: Anees Chagpar, Aula Abbara, Alaa Alshemali, Fares Alahdab, Moahmed Hamze, Bassel Attassi, Jude Alawa, Sydney Cech, Lawrence Tang, Kaveh Khoshnood. BREAST CANCER DIAGNOSIS AND TREATMENT AMONG DISPLACED AND HOST POPULATIONS IN NORTH-WEST SYRIA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-11.
Abstract PO5-11-01: Audit of multidisciplinary team meetings for improving breast cancer care
Authors: Kanika Sharma, Gopal Puri
Journal: Cancer Research (2024)

Abstract Introduction: Multidisciplinary team (MDT) meeting is a well-established method of optimising care for breast cancer patients. However, its effectiveness has not been proven yet. The present study aims to audit the functioning of MDT at a tertiary care hospital in a low-middle income country. Methods: This study examines the prospectively maintained database of patients being discussed in MDT meetings occurring from August 2018 till June 2023. The MDT was suspended for few months in between owing to the COVID pandemic. The analysis was done in terms of indications of discussion, referring department, modification in the pre-MDT plan, new investigation advised, radiological and pathological concordance, significant change in management strategy and interesting cases. The analysis is both qualitative and quantitative. Quantitative analysis involves percentages, mean and median. Results: MDT at our institute was conducted every Saturday at 12 noon as an in-person meeting. The MDT was suspended from May 2020 till June 2021 in view of the pandemic. It was restarted in July 2021, on an online platform and is continued as such. A total of 473 cases were discussed with 181 (38.2%) benign causes and rest were malignant. The most common indication of discussion for malignant cases was feasibility of breast conservation (59.9%) followed by ruling out recurrence/residual disease (17.4%). The indication for benign cases was rad-path concordance and ruling out phyllodes in a case of fibroepithelial lesion. In 31.4% of the cases the plan was modified from the pre-MDT plan and there was improved care. 34.7% cases were advised to get a new investigation done in form of contrast enhanced mammogram or MRI. Seventy nine percent cases were feasible for BCS, and it was done involving few complex surgeries as well. The most common indication for deferring BCS was extensive DCIS. The total number of man hours spent in preparation as well as MDT were analysed with improved clinical care and revealed the MDT to be a time intensive exercise with poor efficacy in terms of hours spent per patient. The time to decision making was increased at an average of 7.5 days for these patients. Conclusion: MDT helps to achieve goals of superior clinical care for both benign and malignant breast disorders at the cost of increased time to decision. It is labour intensive with capability of changing decision in one third of the cases. However, MDT needs regular audit to ensure optimum care with available resources. Citation Format: Kanika Sharma, Gopal Puri. Audit of multidisciplinary team meetings for improving breast cancer care [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-11-01.
Abstract PO4-23-04: Is breast-conserving surgery an optional local therapy for non-inflammatory skin involvement (T4b) breast cancer? A Propensity Score Matching and Inverse Probability Weighting Analysis of SEER Database Results
Authors: Jingyi Lin, Shiping Luo, Jie Zhang, Chuangui Song
Journal: Cancer Research (2024)

Abstract Introduction: Although breast-conserving surgery (BCS) usage has been widespread in breast cancer treatment, it is still controversial about its application in non-inflammatory skin involvement (T4b) breast cancer. We designed this study to compare the prognosis for BCS versus mastectomy in this population. Methods: This retrospective cohort study included patients from the SEER database diagnosed with tumor stage T4b breast cancer from 1998 to 2019. To create prognostic factors, balance between BCS+RT and Mastectomy+RT groups, we calculated propensity scores for each patient. The calculation was based on the advance assessment for factors affecting prognosis, with the use of univariable and multivariable Cox proportional hazards models. Based on it, two propensity score-based matchings were conducted, including propensity score matching (PSM) and inverse probability weighting (IPTW). After adjustment, we performed Kaplan-Meier curves and multivariable Cox proportional hazards models to estimate BCSS and OS. Results: Of 4,680 patients who met the criterion, 588 received BCS+RT, and 4092 received Mastectomy+RT. In the propensity score matching (PSM) cohort, BCS+RT was found to improve breast cancer cause-specific survival (HR, 0.67; 95% CI, 0.53 to 0.85; p=0.001) and overall survival (HR, 0.72; 95% CI, 0.59 to 0.88; p=0.001). Similar results in the analysis of the IPTW-matched cohort confirm this result (BCSS: HR, 0.672; OS: HR, 0.722). Subgroup analysis revealed that those less than 70 years old, grade I+II, 3cm or smaller tumor size, hormone receptor-positive, or received chemotherapy treatment were more likely to benefit from BCS+RT (all p&amp;lt; 0.05). Conclusions: Locally treatment with BCS usage presented a significantly better survival than with mastectomy for non-inflammatory skin involvement (T4b) breast cancer patients. This finding provided evidence of selection in the local treatment of these patients. Citation Format: Jingyi Lin, Shiping Luo, Jie Zhang, Chuangui Song. Is breast-conserving surgery an optional local therapy for non-inflammatory skin involvement (T4b) breast cancer? A Propensity Score Matching and Inverse Probability Weighting Analysis of SEER Database Results [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-04.
Abstract PO4-23-07: Impact of distance between tumor and nipple on locoregional recurrence in breast cancer
Authors: Jong-Ho Cheun, Eunhye Kang, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han, Ki-Tae Hwang
Journal: Cancer Research (2024)

Abstract Introduction: Mastectomy is usually recommended for centrally located tumors due to the risk of nipple invasion. While it is well known that there is no significant difference in survival outcomes according to tumor location, central tumors have a higher likelihood of main lactiferous duct invasion, which can result in the migration of tumor cells to the periphery. Therefore, we conducted an investigation specifically focusing on locoregional recurrence (LRR) rates based on the tumor-to-nipple distance (TND). Method: We retrospectively collected the data of patients who underwent breast cancer surgery between 2004-2018 from two institutions. Patients who underwent neoadjuvant chemotherapy were excluded. TND information was obtained from preoperative MRI records. Results: A total of 9,014 patients were included in the study, and the median tumor-to-nipple distance (TND) was 3.4 (0.0-15.0) cm. For all patients, the restricted cubic spline curve analysis showed that the hazard risk of LRR increased with shorter TND. The pattern was more pronounced in the breast-conserving surgery (BCS) group, whereas the mastectomy group showed a relatively constant risk regardless of TND. Thus, we conducted survival analysis for 5,455 patients who underwent BCS. We set the cutoff for TND as 2.5cm as it showed the lowest p-value for LRR rate. Compared to those with TND &amp;gt;2.5cm, patients with TND≤2.5cm showed significantly lower LRR (HR,1.83;95%CI,[1.37-2.46],p&amp;lt; 0.001) and distant metastasis(DM) (HR,1.53;95%CI,[1.16-2.02],p=0.002) rates. Overall survival was not different between two groups (p=0.405). Cox-regression analysis revealed that TND still impacts LRR (HR,1.52;95%CI,[1.11-2.09],p=0.010) but not DM. Importantly, TND still remained significant factor affecting LRR when analyzed as continuous variable (HR,1.04; 95%CI,[1.02-1.06],p&amp;lt; 0.001). The prognostic impact of TND was particularly evident in patients with high mammographic density. Discussion: BCS can be performed for centrally located tumors, as it offers considerable oncologic safety compared to mastectomy. However, for patients who have a fear of recurrence and are reluctant to undergo re-operation, mastectomy would be a good choice. Citation Format: Jong-Ho Cheun, Eunhye Kang, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han, Ki-Tae Hwang. Impact of distance between tumor and nipple on locoregional recurrence in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-07.