bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO3-01-14: Impact of detection mode, tumor characteristics and additional treatment on adherence to adjuvant endocrine therapy after breast cancer in Sweden
Authors: Andersson Anne , Von Wachenfeldt Anna , Nyström Lennarth , Isaksson Frida , Ruohonen Pihla
Published: May 2024

Background: Adjuvant endocrine therapy (AET) reduces recurrence and mortality in women with estrogen receptor (ER) positive early breast cancer (EBC). Adherence to AET has been shown to be lower than expected with risk of worse longtime prognosis. In a nationwide study in Sweden women with breast cancer diagnosis 2008-2010 adherence to AET at 5-year follow-up was estimated at 82,5% which is considered good related to recent published studies (manuscript is under review). Differences between regions and age-groups were shown. Present study investigates the impact on adherence of detection mode, tumor characteristics and additional treatment. Methods: Through the Swedish Cancer Registry (SCR) women with a first primary EBC diagnosed 2008-2010 were identified. From the Swedish National Breast Cancer Registry (NKBC) individual tumor and treatment data were collected. Included in the study was patients with ER positive tumors > 10 mm without distant metastasis at diagnosis. Through the Swedish Prescription Registry dispensed treatment from pharmacies was extracted and medication possession rate (MPR) was calculated as number of dispensed doses divided by treatment duration in days. Good adherence to treatment in a patient was set at MPR ≥80%. Adherence at 3- and 5-year follow-up by detection mode, tumor characteristics and additional treatment was estimated. Results: Out of 21 016 women with a first primary BC 2008-2010 registered in the NKBC 10 176 met the inclusion criteria for the study. Among screen-detected tumors the 3- and 5-year adherence were 90,2 respectively 85,1% and 85,4 respectively 78,4% in the non-screen-detected group. In the screen-detected group the tumors were smaller and more often node negative. There was a significantly increased 5-year adherence in patients with stage III disease compared to those with stage I disease (84,1 vs 81,3 %) but not significant at 3-year (89,2 vs 87,3). Adjuvant chemotherapy significantly increased 3- (91.0% vs 85.8%) and 5-year (85.7% vs 79.3%) adherence among screen-detected and non-screen-detected respectively. Conclusions: Adherence to AET in Sweden was good, although there were differences depending on detection mode, tumor stage and additional adjuvant treatment. Stage and additional medical adjuvant treatment depend on each other and should not be seen as independent factors for adherence for AET.

Citation Format: Anne Andersson, Anna Von Wachenfeldt, Lennarth Nyström, Frida Isaksson, Pihla Ruohonen. Impact of detection mode, tumor characteristics and additional treatment on adherence to adjuvant endocrine therapy after breast cancer in Sweden [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-14.
Abstract PO3-15-01: Overexpression of N-glycosylation related gene OST4 promotes chemotherapy resistance in triple-negative breast cancer
Authors: Wang Wei , Liu Deyue , Ding Shuning , Fang Yan , Wu Jiayi , Zhu Li
Published: May 2024

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with high malignancy and poor outcome. Resistance to chemotherapy leads to treatment failure. How to overcome drug resistance is the key point in TNBC treatment. Previously, we initiated a prospective multicenter single-arm NeoPath clinical study (ClinicalTrial.gov identifier: NCT03907800) to assess the efficacy and safety of nab-paclitaxel combined with carboplatin in the neoadjuvant therapy of triple negative and HER2-positive early breast cancer. A total of 99 TNBC patients were enrolled and the pCR rate in TNBC was 33.78%. Samples before and after treatment were collected. RNA-sequencing results showed that OST4 was of high-expression in drug-resistant TNBC tumor tissues compared with chemo-sensitive samples. To verify the clinical significance of OST4 expression levels in TNBC, we tested the expression of OST4 by immunohistochemical technique on a tissue microarray including 87 TNBC cases treated with chemotherapy. We found that high expression of OST4 was associated with poor tumor differentiation, and patients with high OST4 expression had more relapse after chemotherapy. Ex-vivo proliferation assay and foci formation assay further confirmed that over-expression of OST4 promoted chemo-resistance, whereas down-regulating OST4 could reverse resistance in TNBC cell lines. As an oligosaccharyltransferase, it is reported that OST4 played parts in N-glycosylation. So we try to elucidate the relationship between N-glycosylation and drug resistance. Glycoproteomics results verified the existence of differential N-glycosylation atlas in drug-resistant tumor tissues compared with drug sensitive samples. NGS1 was identified as a potential target of OST4 by co-immunoprecipitation and mass spectrometry. In conclusion, high expression of OST4 could promote chemotherapy resistance in TNBC trough N-glycosylation regulation. Targeting OST4 may help reverse drug-resistance and improve therapeutic effect in TNBC.

Citation Format: Wei Wang, Deyue Liu, Shuning Ding, Yan Fang, Jiayi Wu, Li Zhu. Overexpression of N-glycosylation related gene OST4 promotes chemotherapy resistance in triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-01.
Abstract PO3-22-05: Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial
Authors: Karlsson Per , Kovács Anikó , Killander Fredrika , Niméus Emma , Holmberg Erik , Tullberg Axel Stenmark
Published: May 2024

Background: With the introduction of antibody-drug conjugates directed against HER2, a new subgroup of tumors with low HER2 expression (1+ or 2+ without amplification) has emerged. HER2 signaling has been implicated in radioresistance in mechanistic studies and is an accepted biomarker of immunogenicity. The study aimed to contrast tumors with low HER2 expression versus zero HER2 expression from a prognostic and radiotherapy-predictive locoregional perspective. Methods: HER2 status was evaluated using immunohistochemistry and SISH in the randomized radiotherapy (RT) cohort, SweBCG91RT, by a board-certified pathologist. HER2-low status was defined as HER2 IHC 1+ or 2+ without amplification, HER2-zero as 0, and HER2-high as HER2 IHC 3+ or SISH amplified. Tumor-infiltrating lymphocytes were assessed on whole-tissue sections and categorized as low (< 10%) or high (≥ 10%). The endpoint was time to ipsilateral breast tumor recurrence (IBTR) as first event. Results: Out of 964 evaluated primary tumors, 433 (44.9%) were classified as HER2-low, 467 (48.4%) as HER2-zero and 64 (6.6%) as HER2-high. TILs levels did not differ between HER2-low and HER2-zero tumors (p=0.33). The hazard ratio for high TILs was 0.79 in HER2-zero tumor (CI 95% 0.43-1.45, p=0.44) and 0.96 in HER2-low tumor (CI 95% 0.56-1.66, p=0.90), and no interaction effect from TILs was observed (p=0.63). The benefit from RT was similar among HER2-low (HR 0.42, CI 95% 0.25-0.72, p=0.001) and HER2-zero tumors (HR 0.31, CI 95% 0.17-0.56, p< 0.001). Conclusions: HER2-low tumors do not differ from HER2-zero tumors regarding the benefit from postoperative RT. Unlike high HER2 expression, low expression is not associated with TILs infiltration. HER2-low tumors likely do not represent a biologically distinct subtype from a locoregional aspect.

Citation Format: Per Karlsson, Anikó Kovács, Fredrika Killander, Emma Niméus, Erik Holmberg, Axel Stenmark Tullberg. Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-05.
Abstract PO3-24-05: Cysteine metabolism related ferroptosis sensitivity in trastuzumab resistant HER2 positive breast cancer
Authors: Yin Yongmei , Hua Yijia , Duan Ningjun , Sun Chunxiao , Yang Fan
Published: May 2024

Background Trastuzumab has shown great effectiveness in HER2 positive breast cancer treatment, but about 50% patients would undergo resistance during or after treatment. Although previous research has suggested several potential reasons for trastuzumab resistance, the metabolic reprogramming during resistance formation remains largely unclear. Here we identified aberrant ferroptosis associated cysteine metabolism in trastuzumab resistant HER2 positive breast cancer, which might become a novel target for overcoming resistance. Methods Trastuzumab sensitive HER2 positive breast cancer cell SKBR3 and resistant JITM1 were obtained for transcriptomics, proteomics, metabolomics and epigenomics analysis. Gene silencing was mediated by siRNAs. CUT&Tag was applied to compare H3K4me3 and H3K27me3 binding regions. DNA methylation levels and different methylated regions were evaluated by WGBS-seq. CRISPRi with dCas9-DNMT3A was applied to regulate specific DNA methylation in CpG islands. Lipid ROS was measured by flow cytometry with BODIPY-C11. Results Joint analyses of transcriptomics and proteomics according to ferroptosis pathways revealed downregulated glutathione metabolism, glutamate transmembrane and homocysteine metabolism processes, as well as upregulated fatty acid metabolism and iron metabolism pathways in JIMT1. Metabolomics verified that JIMT1 increased cysteine metabolism and decreased glutathione metabolism. SLC7A11 expression and GSH/GSSG ratio were increased in JIMT1, while no difference was observed in free cysteine. JIMT1 featured significant higher UGC codon usage bias and increased cysteinyl-tRNA synthetase. The abundance of H3K4me3 other than H3K27me3 in SLC7A11 promoter region was found increased in JIMT1, and the 5-mC level of CpG islands in SLC7A11 promoter region was shown decreased. Using dCas9-DNMT3A, the methylation of SLC7A11 promoter was enhanced and SLC7A11 expression was reduced in JIMT1. Inhibition of SLC7A11 by siRNAs, CRISPRi or Erastin all indicated a higher ferroptosis sensitivity in JIMT1. Conclusion Trastuzumab resistant HER2 positive breast cancer features aberrant cysteine metabolism resulting from altered H3K4me3 modification and DNA methylation in SLC7A11 promoter region. This might provide novel targets for further anti-HER2 treatment.

Citation Format: Yongmei Yin, Yijia Hua, Ningjun Duan, Chunxiao Sun, Fan Yang. Cysteine metabolism related ferroptosis sensitivity in trastuzumab resistant HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-05.
Abstract PO3-24-08: Establishment of a selective culture method for breast cancer stem cells derived from patient tissue and a subgroup analysis of cancer stem cells
Authors: Sueoka Satoshi , Kadoya Takayuki , Azusa Kai , Sasada Shinsuke , Emi Akiko , Okada Morihito , Kobayashi Yukino , Nakayama Koh
Published: May 2024

Purpose

Cancer stem cells are considered to cause recurrence and metastasis due to their resistance to drug and radiation therapy. Breast cancer stem cells are therefore the true target for the treatment of breast cancer. In this study, we established a method to selectively culture breast cancer stem cells from patient-derived breast cancer tissue, and we analyzed their characteristics using immunostaining to identify gene expression.

Method

Breast cancer tissues from ER+, HER2- and drug-naive patients were fragmented and cultured using low-adherent plates (spheroid culture). We investigated the stemness of the breast cancer cells obtained by the spheroid culture by immunostaining the breast cancer stem cell markers and examining their proliferation and differentiation in a mouse transplantation model. The diversity of the cells was further examined by means of the expression of the EMT markers and genetic analysis.

Results

In 48 cases, the proportion of CD44+/CD24- breast cancer cells increased from 13.8% to 61.6% in the spheroid culture. In addition, even small numbers of cells obtained by the spheroid culture were transplanted into mice, and the transplanted cells subsequently differentiated in the mice, demonstrating their stemness. ER expression was negatively changed in 52.1% of cases, and the expression of EMT markers, Twist, Snail, and Vimentin, was increased from 43.8% to 75.0%, 12.9% to 58.1%, and 7.71% to 37.7%, respectively. A DNA microarray with 14 cases showed that breast cancer stem cells obtained from ER+ and HER2- breast cancer tissue were classified into two groups.

Conclusion

We demonstrated that breast cancer stem cells were selectively cultured from patient-derived breast cancer tissue in a spheroid culture. Furthermore, breast cancer stem cells have different characteristics from breast cancer cells in primary tumors and are diverse at an EMT level, and in genetic analyses.

Table. Expression of primary tumors and spheroids

Citation Format: Satoshi Sueoka, Takayuki Kadoya, Kai Azusa, Shinsuke Sasada, Akiko Emi, Morihito Okada, Yukino Kobayashi, Koh Nakayama. Establishment of a selective culture method for breast cancer stem cells derived from patient tissue and a subgroup analysis of cancer stem cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-08.
Abstract PO3-26-01: Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitor
Authors: Smith Aaron C. , Arwood-Levine Ben , Born Alexandra , Brizendine Richard , Chatterjee Payal , Chicarelli Mark J. , Conner Michael L. , Fell Brad , Fulton Jennifer , Guarnieri Anna , Jalluri Ravi , Knox Hailey , Koch Keith , Krischlunas Daniel , Kumar Vijay , McHugh Colin , Mclean Brent , Nassar Kelsey , Newhouse Brad , Rieger Rob , Robinson John , Rodriguez Marelí , Salituro Leah , Stunkard Lee , Sullivan Francis , Turton Roy , Winski Shannon , Zhou Yeyun
Published: May 2024

The PI3K pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. Specifically, the H1047R and helical domain mutations E542K/E545K of the p110α subunit of PI3K are known activating mutations that are targeted by inhibitors under clinical investigation as well as by approved drugs. PI3Kα mutations are prevalent in patients with breast, colorectal, lung, endometrial, and numerous other cancers. The approved PI3Kα inhibitor, alpelisib, shows promise for this targeted class with improvements in progression-free survival in HR+/Her2- breast cancer in combination with fulvestrant. However, tolerability concerns such as hyperglycemia, gastrointestinal issues, and skin reactions have emerged related to on-target inhibition of wild type PI3Kα. These issues likely limit dose administration leading to exposure which is suboptimal for maximal efficacy and creates an opportunity to identify an inhibitor with an improved tolerability profile that targets oncogenic mutations while sparing wild type PI3Kα. Herein, we present preclinical in vitro and in vivo activity of a novel, wild type sparing PI3Kα inhibitor which is potent against the oncogenic H1047R mutation.

Citation Format: Aaron C. Smith, Ben Arwood-Levine, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, Brad Fell, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Hailey Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Colin McHugh, Brent Mclean, Kelsey Nassar, Brad Newhouse, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Lee Stunkard, Francis Sullivan, Roy Turton, Shannon Winski, Yeyun Zhou. Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitor [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-01.
Abstract PO3-26-02: Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Authors: Chicarelli Mark J. , Arwood-Levine Ben , Bettendorf Tanna , Bouhana Karyn , Brizendine Richard , Cable LouAnn , Crow Michelle , Fell Brad , Fischer John , Fulton Jennifer , Guarnieri Anna , Hillman Madison , Jalluri Ravi , Krischlunas Daniel , Koch Keith , Kumar Vijay , Malinky Cori , Rieger Rob , Robinson John , Stunkard Lee , Sullivan Francis , Turton Roy , Vine Logan , Winski Shannon , Zhou Yeyun
Published: May 2024

Alterations in ErbB2 have an established role as oncogenic drivers in many solid tumors, including gastric and breast cancer. While ErbB2 amplification is well recognized, activating ErbB2 mutations including exon 20 YVMA insertions, S310F/Y, L755S, V777L, and V842I, have emerged as mutually exclusive oncogenic drivers. ErbB2 mutations are present in ~3-4% of breast cancers and are now recognized as known mechanisms of acquired resistance to ErbB2 targeted therapies. These alterations can also be found in metastastic breast cancer that has advanced to the brain, a major clinical challenge with few therapeutic options. Unfortunately, many approved ErbB2 inhibitors are limited in their utility due to the inhibition of wild type EGFR resulting in severe rash and diarrhea. Herein, we describe preclinical data on a brain penetrant, wild type EGFR sparing, ErbB2 inhibitor with activity against prevalent mutations including exon 20 YVMA insertions.

Citation Format: Mark J. Chicarelli, Ben Arwood-Levine, Tanna Bettendorf, Karyn Bouhana, Richard Brizendine, LouAnn Cable, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Madison Hillman, Ravi Jalluri, Daniel Krischlunas, Keith Koch, Vijay Kumar, Cori Malinky, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, Roy Turton, Logan Vine, Shannon Winski, Yeyun Zhou. Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-02.
Abstract PO3-28-05: Therapeutic Plasmapheresis as a Symptomatic Treatment for Paclitaxel-Associated Peripheral Polyneuropathy
Authors: Abdugafforov Sardor , Vorotnikov Vladimir , Soynov Alexander , Mchedlidze Tornike , Kopytich Igor , Kim Sofia
Published: May 2024

Relevance: Paclitaxel-associated peripheral polyneuropathy (PIPN) is one of the most common side effects that develop during treatment with drugs of the taxane group. In the treatment of early breast cancer with paclitaxel 80 mg/m2 weekly, 12 injections, PINP develops in 90% of patients of varying severity. The main symptoms are pain and numbness in the arms and legs, which is associated with the accumulation of paclitaxel in the ganglia of the spinal cord, as well as increased expression in the ganglia of the spinal cord of chemokines and cytokines, such as IL-1β, IL-8 and TNF-α, as well as CXCR4, RAGE, CXCL1, CXCL12, CX3CL1 and C3. We hypothesized that the severity of PIPN symptoms can be reduced by lowering the concentration of chemokines and cytokines in the blood by performing plasmapheresis sessions. Research methods: An open prospective study was carried out, the protocol of which was approved by the ethical committee. The study included 30 patients (100% women) aged 30 to 60 years (mean age 45 years) who developed PIPN during paclitaxel therapy 80 mg/m2, weekly, 12 injections. The severity of PIPN symptoms was assessed using a “visual analogue scale” (VAS). The results of the VAS evaluation varied from 6 to 8 points. Patients underwent 5 courses of membrane plasmapheresis with exfusion of 400-500 ml of plasma per session (20 ml per 1 kg of body weight), plasma loss was compensated with saline. Repeated procedures were performed once every two months for 6 months. Results: 30 patients underwent 15 procedures of therapeutic plasmapheresis within 6 months. In 21 patients (70%) there was a pronounced decrease in PIPN symptoms (VAS - 2-3 points), in 3 patients (10%) a moderate decrease in symptoms (VAS -5-6 points), in 6 (20%) no effect of plasmapheresis (VAS - 7-8 points). Approximately 15% of procedures were associated with adverse events, the most common of which were vasovagal reactions; 20% of patients had at least one adverse event. Conclusions: Given the subjective reduction in the severity of PIPN symptoms during courses of therapeutic plasmapheresis in more than 70% of cases, therapeutic plasmapheresis can be used as a symptomatic therapy for PIPN, however, taking into account the subjective assessment of the results by patients, there may be a risk of developing cognitive errors. Therefore, this method of therapy requires more thorough study.

Citation Format: Sardor Abdugafforov, Vladimir Vorotnikov, Alexander Soynov, Tornike Mchedlidze, Igor Kopytich, Sofia Kim. Therapeutic Plasmapheresis as a Symptomatic Treatment for Paclitaxel-Associated Peripheral Polyneuropathy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-05.
Abstract PO3-28-11: Potassium channel activity unveils breast cancer vulnerability
Authors: Gentile Saverio
Published: May 2024

Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiological and pathological conditions and have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that breast cancer downregulates expression of specific potassium channels (e.g., Kv11.1, KCa3.1) independently of their molecular characterization (ER+, HERB2+ and TNBC). Furthermore, breast cancer patients expressing high protein level of each of these channels presents a better overall survival when compared with patients with low expression. These data indicate that potassium channels can be prognostic factors and that high activity of these protein affects tumor growth. Therefor we wanted to understand the therapeutic benefits of pharmacological targeting specific potassium channels in breast cancer. We discovered that stimulation of the Kv11.1 with specific and selective activator molecules produced a significant growth arrest in a variety of experimental systems including in vitro, in vivo and ex vivo (e.g. Patient-derived organoids) systems. Studying the biochemical pathways that underline these events we discovered that Kv11.1 agonists affects different hallmarks of cancer including metabolism, growth and metastasis signaling without producing significant side effects. For example, use of Kv11.1 agonists produced a strong suppression of oncogene protein function including c-Myc while increasing oncosuppressors such as p21 and p16. These events associated with activation of a senescent phenotype. Furthermore, stimulation of Kv11.1 channel reversed the epithelial-to-mesenchymal transition by inhibiting the WNT signaling and reduced spreading of a TNBC by arresting the metastatic process.. Furthermore, Kv11.1 activation produced a Ca2+-dependent mitochondria damage where the antioxidant transcription factor NRF2 played a fundamental role in determining resistance to death. Therefore, we conclude that targeting the Kv11.1 potassium channel in breasts cancer can be considered a new, effective and safe targeting strategy for breast cancer.

Citation Format: Saverio Gentile. Potassium channel activity unveils breast cancer vulnerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-11.
Abstract PO4-01-04: Clinical significance of Circulating tumor DNA (ctDNA) analysis in predicting pathologic complete remission in HER2-positive Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy
Authors: Kang Byeongju , Lee Soo Jung , Lee Jeeyeon , Lee In Hee , Park Jee-Young , Park Ho Yong , Zheng Tiantian , Tan Lu , Chung Liam Il-Young , Jia Shidong , Du Pan , Chae Young Kwang , Chae Yee Soo
Published: May 2024

Background: Neoadjuvant chemotherapy (NACT) combined with dual anti-HER2 agents followed by surgical resection is the standard treatment for stage II-III HER2-positive breast cancer. Despite the availability of effective therapies as an adjuvant treatment such as ado-trastuzumab emtansine (T-DM1) and neratinib, pathologic complete remission (pCR) strongly predicts survival. This study aimed to investigate the role of ctDNA analysis in predicting pCR and clinical outcome using comprehensive ctDNA analysis.

Methods: A total of 34 HER2-positive breast cancer patients who underwent NACT combined with dual anti-HER2 agents and surgical resection were enrolled, including 22 clinical stage II and 12 III patients. Plasma samples were collected at four-time points: before neoadjuvant chemotherapy, after 3 cycles, at the completion of neoadjuvant chemotherapy, and after surgery. low-pass whole-genome sequencing (lpWGS) and whole exome sequencing (WES) in evaluating blood copy-number burden (bCNB), genomic alterations, mutational signatures, blood tumor mutational burden (bTMB). Mutations selected from the baseline sample were monitored for Molecular residual disease (MRD) monitoring. lpWGS yielded negative results, targeted NGS sequencing was conducted.

Results: Among the enrolled patients (N=34), 21 patients (61.8%) had nodal metastasis and 22 patients (64.7%) were hormone receptor-positive. A total 26 patients (76.5%) achieved pCR. Positive ctDNA was detected in 20 patients (58.8%) at baseline. Higher nodal stage was significantly associated with ctDNA positivity at baseline. After surgery, MRD positivity was observed in 3 patients (8.8%). Among the 26 patents who acheived pCR, only 1 patient (3.8%) showed MRD positivity, while 2 non-pCR patients (25%) demonstrated MRD positivity.

Conclusion: The presence of MRD was significantly associated with non-pCR status. The presence of ctDNA at baseline was associated with a higher nodal stage, suggesting its potential as a prognostic marker. Further studies with larger cohorts are warranted to validate these findings and explore the utility of ctDNA analysis for personalized treatment decisions in HER2-positive breast cancer.

Citation Format: Byeongju Kang, Soo Jung Lee, Jeeyeon Lee, In Hee Lee, Jee-Young Park, Ho Yong Park, Tiantian Zheng, Lu Tan, Liam Il-Young Chung, Shidong Jia, Pan Du, Young Kwang Chae, Yee Soo Chae. Clinical significance of Circulating tumor DNA (ctDNA) analysis in predicting pathologic complete remission in HER2-positive Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy [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 PO4-01-04.
Abstract PO4-05-10: A Carryover Effect: Antibody Drug Conjugates Constantly Provide a Substantial Improvement in Overall Survival more than in Progression-free Survival
Authors: Chen I-Chun , Lin Ching-Hung , Lu Yen-Shen
Published: May 2024

Background: In metastatic breast cancer (MBC), progression-free survival (PFS) improvement does not always translate into overall survival (OS) benefit. Multiple treatment options after progression resulted in a long post-progression survival in MBC patients, and these would make the dissociation of PFS benefit and OS benefit. We have reported the constant correlation of PFS improvement and OS improvement in anti-HER2 containing treatment (Breast 2021; 59:211-220). The relationship between PFS and OS improvement in antibody drug conjugate has not been thoroughly examined.

Methods: “Metastatic breast cancer” and “antibody drug conjugate” (ADC) were used as keywords to search for randomized clinical trials that report both PFS and OS. Hazard ratios (HR) and median survival were analyzed. Increments in PFS (delta PFS) and increments in OS (delta OS) were compared between studies.

Results: A total of 8 trials were identified and summarized in table 1. The target of ADC was HER2 (N=6) or Trop2 (N=2). In DESTINY-Breast 03 trial, the control arm was another ADC (T-DM1). The control arms in all the other 7 trials were chemotherapy. The HR of PFS (range 0.28-0.66) was smaller than HR of OS (range 0.48- 0.83) in all of the trials. The median OS was not reached (NR) in 1 of the trials (DB-03) and was thus removed from the analysis for delta PFS and delta OS. In the comparison of delta PFS, the increments of median PFS fell between 1.5 and 10.9 months(m). The increments of median OS were between 1.6 and 12.7 m. All the delta OS are greater than the delta PFS in the 7 trials with available PFS and OS data.

Conclusion: In MBC, ADCs targeting HER2 and Trop2 both constantly provide improvement of OS greater than PFS. Further investigation on the potential mechanism is warranted.

Table 1

Citation Format: I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu. A Carryover Effect: Antibody Drug Conjugates Constantly Provide a Substantial Improvement in Overall Survival more than in Progression-free Survival [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 PO4-05-10.
Abstract PO4-10-08: Building a standard methodology: Early Gynecologic Consultation and Bone Mass Density Examination in Breast Cancer Patients Receiving Endocrine Therapy
Authors: Ching-Wen Chiu , Ka-Wai Tam , Chih-Ming Su , Hsueh-Chi Wu
Published: May 2024

Purpose

Hormone receptor-positive type of breast cancer is typically treated with hormone therapy (HT), including tamoxifen and aromatase inhibitors (AI). However, long-term use of HT may increase the risks of endometrial cancer, vaginal dryness, and osteoporosis. To minimize the risks, breast surgeons should schedule regular follow-up with gynecologists and arrange bone mass density (BMD) examination. Using the Plan-Do-Study-Act (PDSA) methodology, we aimed to increase cross-team care with gynecology department and to promote BMD examination for breast cancer patients receiving HT.

Methods

We formed a multidisciplinary team including breast surgery department and gynecologic department in our hospital that care for female patients with breast cancer and related side effects. We arranged a lecture for all collaborative doctors, introducing our aims, interventions, and measurement strategies to test in multiple PDSA cycles. The interventions with standardized criteria include: (1) a gynecologic consultation, triggered if a patient initially receive tamoxifen and (2) a BMD examination, triggered if a patient initially receive AI. The triggering mechanism is embedded in the ambulatory alarming system. Both the intervention rates were tracked during PDSA cycle 1 in 2023 and compared with baseline rates in 2020-2022. Adherence to the plan was maintained and measured using data analytic reports and chart audits.

Results

The gynecologic consultation rate during PDSA cycle 1 is significantly higher than the baseline, which is 40.4% and 22.4% (p = 0.006), respectively. In patients who received tamoxifen, 6-month-consultation rate during PDSA cycle 1 is also significantly higher than the baseline group, which is 77.77% and 42.9% (p = 0.005), respectively. The median time from HT therapy to first gynecologic consultation decreased from 51 days to 28 days. Furthermore, the baseline BMD testing rate before our intervention was 30.6%. This increased to 48.3% during PDSA cycle 1.

Conclusion

Standardized gynecologic consultation criteria led to earlier gynecologic consultation in breast cancer patients receiving tamoxifen and higher BMD test rates in patients receiving AI. Future PDSA cycles will focus on assessing the frequency of subsequent gynecologic encounters in patients who received a triggered gynecologic consult.

Citation Format: Chiu Ching-Wen, Tam Ka-Wai, Su Chih-Ming, Wu Hsueh-Chi. Building a standard methodology: Early Gynecologic Consultation and Bone Mass Density Examination in Breast Cancer Patients Receiving Endocrine Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-08.
Abstract PO4-13-01: A randomised trial comparing 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early breast cancer (REaCT-ZOL): Quality of life and toxicity outcomes
Authors: Machado Igor , Clemons Lucas , Stober Carol , Pond Gregory , Awan Arif , Conter Henry , Simos Demetrios , Dhesy-Thind Sukhbinder , Mates Mihaela , Kumar Vikaash , Hilton John , Vandermeer Lisa , Clemons Mark
Published: May 2024

Background: While adjuvant 6-monthly zoledronate is widely used in patients with early-stage breast cancer (EBC), questions remain around optimal scheduling of adjuvant bisphosphonates. We reviewed quality of life and bisphosphonate-related toxicities observed within a prospective randomised trial.

Methods: Patients with EBC were randomised to either a single infusion of adjuvant zoledronate (4mg IV) or to 6-monthly treatment for 3 years. Quality of life was measured using the EQ-5D-5L questionnaire (before and after each infusion and 6-monthly thereafter in the single infusion arm). Acute phase reaction (APRs) data was collected after each infusion and data on other bisphosphonate-related toxicities (hypocalcaemia, renal impairment, ONJ and atypical fractures) was collected 6-monthly for 3 years.

Results: Between 21-Nov-2018 and 02-Apr-2020, 211 patients were randomized to either a single infusion (n=107) or 6-monthly (n=104) adjuvant zoledronate. While each zoledronate infusion was associated with a worsening QoL, the overall QoL was the same in the two study arms. APRs occurred in 75% of patients after receiving zoledronate. Other bisphosphonate-related toxicities were uncommon in either arm. Significantly more patients discontinued study treatment in the 6-monthly arm (30/104, 28.8%) compared with the single infusion arm (3/107, 2.8%) (p < 0.001). The most common reason for study discontinuation was the occurrence of APRs, pain and malaise. Disease-free and overall survival rates were not significantly different in the study arms.

Discussion: A single infusion of adjuvant zoledronate may offer patients a more convenient and better tolerate regimen than repeat infusions. APRs remain an important toxicity with repeat infusions of zoledronate, leading to increased rates of treatment discontinuation. Larger, definitive, trials comparing a single infusion with repeat treatments are required.

Citation Format: Igor Machado, Lucas Clemons, Carol Stober, Gregory Pond, Arif Awan, Henry Conter, Demetrios Simos, Sukhbinder Dhesy-Thind, Mihaela Mates, Vikaash Kumar, John Hilton, Lisa Vandermeer, Mark Clemons. A randomised trial comparing 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early breast cancer (REaCT-ZOL): Quality of life and toxicity outcomes [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 PO4-13-01.
Abstract PO4-17-09: Epidemiological Analysis and Overall Survival of Male Breast Cancer in a Developing Middle Eastern Country Over 18 Years
Authors: Abdulelah Zaid , Abdulelah Ahmed , Alhajahjeh Abdulrahman , Ghazzawi Ahmad , El-Amayreh Layla , Abdel-Razeq Hikmat
Published: May 2024

Background: despite the profound rarity of breast cancer in males, it remains of importance given the associated morbidity and mortality, including the association with worse prognosis than female patients. Nonetheless, male breast cancer epidemiology remains poorly studied in middle eastern populations.

Methodology: This retrospective cohort study examined male patients aged 15 to 85 years who were diagnosed with breast cancer between 2000 and 2018, using data from the Jordan Cancer Registry. Kaplan-Meier analysis was performed to assess the 5-year overall survival of the patients over time.

Results: A total of 22,600 patients were diagnosed with breast cancer since 2000 in Jordan, of which 362 (1.6%) patients were males. 39.8% of male breast cancer cases occurred in the right breast, while the left breast was affected in 43.4% of the cases, and 3.3% of the cases were bilateral. Meanwhile, laterality was not mentioned in 13.5% of registry records.

All male breast cancer cases were malignant in origin with the breast being the primary cancer. Most male patients had grade II (N=112, 30.9%) followed by grade III breast cancer (N=88, 24.3%).

Among the male breast cancer cohort, 224 (62.2%) were treated with surgical intervention, 103 (28.8%) patients were given chemotherapy, 84 (23.4%) patients had radiotherapy and 24 (6.70%) patients had hormonal therapy.

27 patients died during the follow up period. The 5-year overall survival rate for the patients was 92.5% (95% CI, 89.9% to 95.3%).

Conclusion: Breast cancer in middle eastern males tends to more commonly present in the left breast, and at a more advanced stage in comparison to females.

Citation Format: Zaid Abdulelah, Ahmed Abdulelah, Abdulrahman Alhajahjeh, Ahmad Ghazzawi, Layla El-Amayreh, Hikmat Abdel-Razeq. Epidemiological Analysis and Overall Survival of Male Breast Cancer in a Developing Middle Eastern Country Over 18 Years [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-09.
Abstract PO4-17-10: Epidemiological Analysis and Overall Survival of Female Adolescent and Young Adults Breast Cancer in a Developing Middle Eastern Country Over 18 Years
Authors: Abdulelah Ahmed , Abdulelah Zaid , Alhajahjeh Abdulrahman , Ghazzawi Ahmad , El-Amayreh Layla , Abdel-Razeq Hikmat
Published: May 2024

Background: Breast cancer is the most common type of cancer among female adolescents and young adults (AYAs) aged 15-39 years at diagnosis. AYAs with breast cancer have worse prognosis and are more likely to present with unfavorable tumor biology. However, breast cancer in AYAs is still poorly reported in middle eastern populations.

Methodology: This is a retrospective cohort study which examined female AYAs patients aged 15 to 39 years at the time of diagnosis who were diagnosed with breast cancer between 2000 and 2018, using data from the Jordan Cancer Registry. Kaplan-Meier analysis was performed to assess the 5-year overall survival of the patients over time.

Results: A total of 3831 Female AYAs were diagnosed with breast cancer in Jordan between 2000 and 2018 with a median age of 34.2 (IQR 30.9-38.3) years. 43.2% of female AYAs breast cancer cases were right breast cancer, whereas left breast cancer occurred in 47.4% of cases, and only 2.15% of cases were bilateral breast cancer. Meanwhile, 7.31% of cases did not have a reported laterality in the registry records.

Most female AYAs patients had high grade breast cancer with grade III breast cancer being the most common (N=1349, 35.2%) followed by grade II breast cancer (N=1093, 28.5%).

Among this female AYA cohort, 2208 (59.3%) were treated with surgical intervention, 1621 (43.5%) patients were given chemotherapy, 1220 (32.7%) patients had radiotherapy, 265 (7.15%) patients had hormonal therapy and only 47 (1.27%) were treated with immunotherapy.

Among the entire studied cohort, 229 (5.98%) patients died during follow up period. The 5-year overall survival was 94% (95% CI 93.3% to 94.8%)

Conclusion: Female AYAs breast cancer tends to have a predilection towards the left breast, but presents at a more advanced grade compared with other age groups in females.

Citation Format: Ahmed Abdulelah, Zaid Abdulelah, Abdulrahman Alhajahjeh, Ahmad Ghazzawi, Layla El-Amayreh, Hikmat Abdel-Razeq. Epidemiological Analysis and Overall Survival of Female Adolescent and Young Adults Breast Cancer in a Developing Middle Eastern Country Over 18 Years [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-10.
Abstract PO4-22-04: Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation
Authors: Shalaby Ahmed , Sherwani Zohaib , Hathout Lara , Jan Imraan , Haffty Bruce , George Mridula , Kumar Shicha , Omene Coral , Toppmeyer Deborah , Ohri Nisha
Published: May 2024

Purpose: Adjuvant capecitabine has been shown to improve disease-free survival and overall survival in breast cancer patients who have residual disease after neoadjuvant chemotherapy, particularly in those with triple negative breast cancer (TNBC). While adjuvant chemotherapy is often completed prior to adjuvant radiotherapy (RT), capecitabine may be administered concurrent with RT to reduce the time from surgery to RT. The purpose of this study was to evaluate the feasibility of concurrent therapy and the associated rates of acute loco-regional toxicity.

Materials and Methods: A retrospective chart review was performed to identify all breast cancer patients who received adjuvant capecitabine and RT. Patients with a history of prior RT, patients who were treated with capecitabine and RT sequentially, and patients who were treated with palliative intent were excluded. Capecitabine was given Monday-Friday during RT. Patient and disease characteristics, capecitabine and RT treatment details, acute toxicity, and treatment breaks were recorded. Toxicity was scored by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Results: A total of 27 patients with non-metastatic breast cancer who received concurrent capecitabine and RT with definitive intent treated from 2013 to 2023 were identified. Median age at diagnosis was 52 years [Interquartile Range (IQR) 40-60]. Adjuvant capecitabine dose ranged from 500-1500 mg twice daily. Adjuvant RT dose ranged from 42.56 Gray (Gy) to 50.4Gy. The majority of patients (92.6%) received a sequential 10-14 Gy boost to the lumpectomy site or mastectomy scar, and 70.3% of patients received elective regional nodal RT. During treatment, all patients developed Grade 1 or 2 radiation dermatitis, while Grade 3 radiation dermatitis was noted in 4 (14.8%) patients. Two patients required a treatment break from RT, and both patients were able to subsequently complete their planned RT course. Seven patients (25.9%) required a capecitabine dose reduction or capecitabine treatment break during RT. No Grade 4 or 5 toxicities were reported. Median follow-up from RT completion was 7 months [IQR 0.98-12.2]. At last follow-up, radiation dermatitis had improved to Grade 0-1 for all patients.

Conclusion: Concurrent adjuvant capecitabine and RT is a feasible treatment approach that is well tolerated with acceptable acute toxicities.

Citation Format: Ahmed Shalaby, Zohaib Sherwani, Lara Hathout, Imraan Jan, Bruce Haffty, Mridula George, Shicha Kumar, Coral Omene, Deborah Toppmeyer, Nisha Ohri. Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation [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 PO4-22-04.
Abstract PO4-23-03: The Influence of Reconstruction Type on Outcomes in Women Undergoing Mastectomy with Immediate Reconstruction: A Nationwide Study
Authors: Hernandez Lucia Castro , Parreco Joshua
Published: May 2024

INTRODUCTION:

Outcomes after mastectomy with immediate reconstruction may vary depending on the type of reconstruction, but the evidence is limited and inconsistent. The purpose of this study was to compare the most common reconstruction techniques in a large national cohort of women undergoing these procedures.

METHODS:

The Nationwide Readmissions Database for 2016-2020 was queried for all women aged 18 years or older undergoing mastectomy for breast cancer with immediate reconstruction. The primary outcome was prolonged length of stay (LOS) greater than 7 days. The secondary outcomes were readmission within 30 days and readmission to a different hospital. The types of reconstruction were compared along with all other relevant variables from the database. Univariable comparison was performed using chi-squared tests for each outcome. Multivariable logistic regression was performed using all significant confounders.

RESULTS:

During the study period, 35,430 patients were identified undergoing mastectomy for breast cancer with immediate reconstruction. The rate of prolonged (LOS) was 2.4% (n= 840) and the readmission rate was 5.4% (n=1,919). From the readmitted patients, the rate of readmission to a different hospital was 14.2% (n=273). Controlling for confounders with multivariable logistic regression revealed the strongest risk factors for prolonged LOS were latissimus dorsi flap (OR 5.4 [4.0-7.4] p< 0.001) and an investor-owned hospital (OR 4.3 [3.5-5.2] p< 0.001). The highest risk of readmission was a transverse rectus abdominis flap (OR 1.3 [1.1-1.6] p< 0.001) and the highest risk of readmission to a different hospital was a small hospital (OR 2.2 [1.6-3.1] p< 0.001).

CONCLUSION:

Reconstruction type influences outcomes in women undergoing mastectomy. These outcomes have significant implications for surgical decision-making and fragmentation of care. Further research to identify ways to reduce adverse outcomes and improve patient satisfaction is warranted.

Citation Format: Lucia Castro Hernandez, Joshua Parreco. The Influence of Reconstruction Type on Outcomes in Women Undergoing Mastectomy with Immediate Reconstruction: A Nationwide Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-03.
Abstract PO4-25-05: LYVE-1 expressing macrophages modulate the extracellular matrix and contribute to mammary tumor growth
Authors: Elfstrum Alexis , Rumahorbo Annisa , McCluskey Braedan , Nelson Emma , Schwertfeger Kaylee
Published: May 2024

Macrophages represent a heterogeneous myeloid population with varied functions in normal tissue and tumors. We identify a tissue resident macrophage subpopulation marked by the protein LYVE-1 in both the female mammary gland and mammary tumor. In a genetic LYVE-1+ macrophage deletion model, loss of LYVE-1+ macrophage leads to accumulation of the extracellular matrix glycosaminoglycan hyaluronan. Further, qRT-PCR of tissue lacking LYVE-1+ macrophages yields a gene signature associated with extracellular matrix disorganization. Supporting a tissue remodeling functionality, inducing a LYVE-1 macrophages phenotype in vitro prompts HA internalization and increases hyaluronidase expression. In a murine tumor model, deletion of LYVE-1+ macrophages slows tumor progression and increases HA accumulation, suggesting an anti-tumorigenic, tissue remodeling phenotype. LYVE-1+ macrophages preferentially localize to HA dense regions of tumors, specifically in the tumor stroma, while scRNA-seq of murine tumors demonstrates a LYVE-1+ macrophage phenotype associated with tissue remodeling and immunosuppression. Our data illustrate a LYVE-1+ macrophage population critical for HA homeostasis and tumor progression.

Citation Format: Alexis Elfstrum, Annisa Rumahorbo, Braedan McCluskey, Emma Nelson, Kaylee Schwertfeger. LYVE-1 expressing macrophages modulate the extracellular matrix and contribute to mammary tumor growth [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 PO4-25-05.