bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract BS1-2: A new perspective on androgen receptor action in estrogen receptor-α positive breast cancer
Authors: Tilley W
Published: March 2022

Resistance to estrogen receptor alpha (ER) target therapies is the major cause of breast cancer death. Therapeutic engagement of steroid receptors that impinge on, but do not ablate, ER signalling is an emerging new treatment strategy. The AR is expressed in the majority of breast tumors and represents an exceptional therapeutic target, especially as a range of drugs including AR agonists, antagonists and selective AR modulators (SARMs) are available. Interest in targeting AR for treatment of breast cancer has escalated over the past decade. Despite clinical correlations and preclinical studies supporting a protective role for AR in breast cancer, especially in ER-positive disease, enthusiasm was largely directed toward antagonizing AR with anti-androgenic drugs used to treat men with prostate cancer, a disease definitively driven by oncogenic AR activity. While some pre-clinical studies supported use of an AR antagonist for ER-positive breast cancer, this strategy has had minimal success in clinical trials. Our most recent preclinical studies using a diverse range of in vivo breast cancer models (Hickey et al, Nature Medicine 2021) provides compelling evidence for (i) AR being a tumor suppressor in ER+ breast cancer, and (ii) an AR agonist, not an antagonist, treatment strategy being the optimal therapeutic approach.

Citation Format: W Tilley. A new perspective on androgen receptor action in estrogen receptor-α positive breast cancer. [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr BS1-2.
Abstract DEB2-2: Con - One Week of Whole Breast RT is the New Standard of Care
Authors: White J
Published: March 2022

The dual role of breast irradiation post lumpectomy for conservative treatment is to yield local cancer control comparable to that achieved with mastectomy while maintaining a sensate and cosmetically acceptable breast. Through application of a linear quadratic equation that characterizes the radiobiological relationship of total dose and dose per fraction to predict efficacy as well as tissue specific toxicity, breast radiation that is equally effective can be delivered with fewer treatments. This has allowed standard post lumpectomy breast radiation to be reduced to 15 -16 treatments from 25-28 with similar efficacy and toxicity confirmed in multiple clinical trials. The recent Fast Forward trial (Lancet 2020; 395: 1613-26) has now further advanced the application of this radiobiological model evaluating breast irradiation delivered in 5 treatments. This resulted in non-inferior recurrence events compared to 15-treatment breast irradiation. When using fewer treatments of larger radiation dose, small changes can result in significant toxicity effects. For example, with 1 Gy difference between 26 Gy and 27 Gy total dose treatment arms on the Fast Forward trial, significantly higher rates of breast adverse outcomes were seen. Additional experience with the 5-fraction breast irradiation is needed prior to its replacing the current 15-16 treatment standard.

Citation Format: J White. Con - One Week of Whole Breast RT is the New Standard of Care [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr DEB2-2.
Abstract ES10-2: Immune therapy in the (neo) adjuvant setting
Authors: McArthur H
Published: March 2022

Historically, the treatment of early-stage triple negative breast cancer (TNBC) has hinged on the administration of conventional cytotoxics. However, the curative-intent treatment landscape has recently evolved with the successful development of checkpoint blockade inhibitor (CPI) strategies. Specifically, on July 27, 2021, the United States FDA approved the PD-1 directed antibody, pembrolizumab, for high-risk early-stage TNBC together with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery based on the results of the randomized, phase 3 KEYNOTE-522 study. In this study, the addition of pembrolizumab to a platinum-, taxane- and anthracycline-based regimen conferred an absolute 13.6% improvement in pathologic complete response (pCR) in the intention-to-treat population at the first interim analysis, with benefits observed irrespective of PD-L1 status. Although the absolute benefit subsequently decreased to 7.5% at the third interim analysis, the event free survival (EFS) benefit was maintained. In fact, with a median follow-up of 39.1 months at the fourth interim analysis, the EFS was 15.7% versus 23.8% (HR 0.63, p= 0.00031) in favor of the CPI containing regimen. The Geparnuevo study, a modestly powered study in which randomized patients with early stage TNBC to receive neoadjuvant chemotherapy with or without durvalumab, a PD-L1 targeting CPI, did not meet its pCR primary endpoint; however, in a recent update reporting on secondary endpoints, improvements in invasive disease free survival (85.6% vs 77.2%), distant disease free survival (91.7% vs 78.4%) and overall survival (95.2% vs 83.5%) were reported in favor of the CPI-containing regimen. EFS data from the IMpassion031 study of neoadjuvant chemotherapy with or without the PD-L1 targeting CPI, atezolizumab, are anticipated after an absolute 16.5% improvement in pCR was reported in the intention-to-treat population with the addition of the CPI, with benefits observed regardless of PD-L1 status. Studies evaluating the role of CPI strategies in the adjuvant setting are also underway. For example, pembrolizumab is being evaluated as monotherapy for patients with residual TNBC after neoadjuvant chemotherapy in the SWOG 1418 study and atezolizumab is being administered with adjuvant chemotherapy after upfront surgery for early-stage TNBC in the IMpassion030/ALEXANDRA study. Studies evaluating curative-intent CPI and targeted therapies and/or local therapies are underway or planned. Available data, current controversies and future directions will be discussed.

Citation Format: H McArthur. Immune therapy in the (neo) adjuvant setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES10-2.
Abstract ES13-3: Novel epigenomic targets in TNBC
Authors: Cescon DW
Published: March 2022

Triple negative breast cancer is a heterogenous disease, characterized by a dearth of recurrent actionable genetic alterations. Epigenetic alterations have been implicated in the pathogenesis of triple negative breast cancer, as well as in the acquisition of drug resistance, which is a commonly observed phenomenon and persisting clinical challenge. An expanding array of tools for epigenomic characterization, together with novel selective inhibitors of epigenetic regulators are enabling new opportunities to identify and target these processes in triple negative breast cancer. Examples of recent and emerging therapeutic strategies using conventional therapies and epigenetic-targeted agents to exploit these vulnerabilities in triple negative breast cancer will be discussed.

Citation Format: DW Cescon. Novel epigenomic targets in TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES13-3.
Abstract ES8-3: Refining axillary management after neoadjuvant chemotherapy - what does the evidence support
Authors: Mamounas P
Published: March 2022

The surgical management of the axilla in patients with operable breast cancer has undergone significant evolution over the past 25 years. Axillary lymph node dissection (ALND), the undisputed standard since the end of the 19th century, has largely been replaced by sentinel lymph node biopsy (SLNB) in most patients with clinically negative axilla with considerable reduction in axillary morbidity. Neoadjuvant chemotherapy (NAC) has been increasingly used in early-stage breast cancer, particularly in patients with triple-negative and HER-2 neu positive tumors. Rates of sterilization of involved axillary lymph nodes with NAC in appropriately selected patients have been steadily increasing with the adoption of more effective NAC regimens. Adoption of SLNB after NAC has lagged behind that of upfront SLNB. Recent data support the feasibility and accuracy of the procedure after NAC in patients who present with clinically negative axilla. Although the accuracy of SLNB is lower after NAC in patients who present with documented involvement of the axilla, identification and removal of the previously biopsied axillary lymph node(s) in addition to performing SLNB (“targeted axillary dissection”) greatly improves the accuracy to levels equivalent to those with upfront SLNB.

Citation Format: P Mamounas. Refining axillary management after neoadjuvant chemotherapy - what does the evidence support [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES8-3.
Abstract MS1-3: Targeting DNA damage response and HRD in breast cancer
Authors: Yap TA
Published: March 2022

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for breast and other cancers. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATR, WEE1, ATM, PK-MYT1, DNA-PK, POLQ and USP1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments, novel molecularly targeted agents and immune-checkpoint inhibitors.

Citation Format: TA Yap. Targeting DNA damage response and HRD in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr MS1-3.
Abstract P1-01-02: Pathologic nodal status is a predictor for metastatic disease in lymph nodes identified by axillary reverse mapping
Authors: Saengphongchawan Rak , Manasnayakorn Sopark
Published: March 2022

Background Breast cancer is the most common cancer in female patients worldwide. Although axillary management in breast cancer has been de-escalated to reduce untoward effects, breast cancer-related lymphedema (BCRL) is still not uncommon. Axillary reverse mapping (ARM) emerges as a novel technique that identifies the lymphatic system draining the upper extremities. Preservation of this system and associated lymph nodes theoretically reduces the chance of BCRL. However, concerns regarding oncologic safety have limited the adoption of the technique. Objective To identify factors associated with metastatic disease in lymph nodes identified by ARM in breast cancer patients. Materials and methods Breast cancer patients treated at King Chulalongkorn Memorial Hospital from October 2018 to January 2021 who underwent axillary lymph node dissection (ALND) underwent concurrent ARM whereby five milliliters of 1% isosulfan blue dye was injected at the medial aspect of the arm as previously described elsewhere. Patient demographics and clinical data such as clinical staging, pathological staging, cancer subtype, and whether neoadjuvant chemotherapy was administered were collected and analyzed. Result Thirty-six patients with a median age of 57 were included in this prospective study. ARM lymph node identification success rate was 83% (30 of 36 patients) with a median of 2 identified ARM lymph nodes (range 0-11 nodes). Metastatic disease in ARM nodes was present in 30% of patients. ARM success rate did not depend on whether preoperative chemotherapy had been given (ARM lymph nodes identified in 7 out of 8 patients without preoperative chemotherapy and 23 out of 28 in patients with preoperative chemotherapy; p=0.36). There was no statistically significant difference in metastatic disease in ARM-identified nodes and clinical stage (stage II=13.3%, stage III=33.3%, and stage IV=50.0%; p=0.18). However, higher pathologic N stage was associated with finding metastasis in ARM-identified lymph nodes (N0=0%, N1=15.8%, N2=33.3%, and N3=80%; p=0.005). Conclusions ARM is a novel technique which can potentially reduce BCRL. However, a significant number of ARM lymph nodes were found to have pathologically-proven metastatic disease, especially in higher pathologic N stages (pN2 and pN3). Therefore, for oncologic safety, consideration should be given to removal of all ARM lymph nodes in breast cancer patients undergoing formal axillary dissection. Keywords: Axillary Reverse Mapping, Axillar dissection, Lymphedema, Breast Cancer

Citation Format: Rak Saengphongchawan, Sopark Manasnayakorn. Pathologic nodal status is a predictor for metastatic disease in lymph nodes identified by axillary reverse mapping [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-02.
Abstract P1-01-04: RUFY3 as a predictive intratumor biomarker for lymph node metastasis in older women with invasive breast cancer
Authors: Angarita Fernando A. , Oshi Masanori , Yamada Akimitsu , Yan Li , Matsuyama Ryusei , Edge Stephen B. , Endo Itaru , Takabe Kazuaki
Published: March 2022

Background: Sentinel lymph node biopsy (SLNB) is omitted in older women (≥ 70 years old) with clinical lymph node (LN)-negative hormone receptor-positive breast cancer as it does not influence adjuvant treatment decision-making. However, older women are heterogenous in frailty while the chance of recurrence increase with improving longevity. Therefore, a biomarker that identifies LN metastasis may facilitate treatment decision-making. RUFY3 is associated with cancer progression. We evaluated RUFY3 expression level as a biomarker for LN-positive breast cancer in older women. Methods: Clinical and transcriptomic data of breast cancer patients were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n=1,903) and The Cancer Genome Atlas (TCGA, n=1,046) Pan-Cancer study cohorts. Results: A total of 510 (METABRIC) and 211 (TCGA) older women were identified. LN-positive breast cancer, which represented 51.4% (METABRIC) and 48.4% (TCGA), demonstrated worse disease-free, disease-specific, and overall survival. RUFY3 levels were significantly lower in LN-positive tumors regardless of age. The area under the curve for the receiver operator characteristic (AUC-ROC) curves showed RUFY3 predicted LN metastasis. Low RUFY3 enriched oxidative phosphorylation, DNA repair, MYC targets, unfolded protein response, and mtorc1 signaling gene sets, was associated with T helper type 1 cell infiltration, and with intratumor heterogeneity and fraction altered. Low RUFY3 expression was associated with LN-positive breast cancer and with worse disease specific survival amongst older women. Conclusion: Low RUFY3 expression is associated LN-positive in breast cancer. Intratumor RUFY levels can be used for selection of older breast cancer patients for LN staging.

Citation Format: Fernando A. Angarita, Masanori Oshi, Akimitsu Yamada, Li Yan, Ryusei Matsuyama, Stephen B. Edge, Itaru Endo, Kazuaki Takabe. RUFY3 as a predictive intratumor biomarker for lymph node metastasis in older women with invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-04.
Abstract P1-02-01: Deep learning identifies morphological changes in whole slide images of treatment-resistant TNBC
Authors: Pour Ali Foroughi , Wu Te-Chia , Martinek Jan , Kumar Swarup , Anzeneder Tobias , Torkler Stephanie , Sommermeyer Franziska , Palucka Karolina , Chuang Jeffrey
Published: March 2022

Deep learning has become an important methodology for analyzing hematoxylin and eosin (H&E) stained whole slide images (WSIs), with high accuracy in detecting tumors, distinguishing cancer subtypes, and stratifying patients by survival risk in certain cancers [1,2,3]. However, machine-learning based evaluations of post-treatment tumors have been limited, e.g. focusing on user-defined features such as cellularity [4] rather than data-driven approaches. We analyzed 80 WSIs to determine if treatment-naïve TNBC, treatment-resistant TNBC, and treatment resistant growth factor and hormone receptor expressing tumors could be distinguished from each other (36 treatment naïve TNBC, 25 resistant TNBC, and 19 resistant non-TNBC WSIs corresponding to 31, 22, and 16 patients, respectively). All resistant patients received chemotherapy, except for one ER+ patient who only received medication to block hormone production. Our deep learning image-based models were able to separate treatment naive and treatment resistant TNBC tumors with high accuracy (AUC=0.85). We further developed a 3-way classifier that was able to distinguish resistant non-TNBC tumors from TNBC treatment-resistant and treatment-naïve samples (AUC=0.74). Removing deep learning features differentiating between TNBC and non-TNBC resistant samples, we find treatment-naïve and resistant samples can be separated irrespective of breast cancer subtype (AUC=0.77). Our results show that post chemotherapy, breast tumors are morphologically distinguishable by machine learning methods from treatment naïve tumors. While some treatment-related morphological changes are present across subtypes, some are unique to TNBC. References:[1] Noorbakhsh, Javad, et al. "Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images." Nature communications 11.1 (2020): 1-14.[2] Wulczyn, Ellery, et al. "Interpretable survival prediction for colorectal cancer using deep learning." NPJ digital medicine 4.1 (2021): 1-13.[3] Cui, Lei, et al. "A deep learning-based framework for lung cancer survival analysis with biomarker interpretation." BMC bioinformatics 21.1 (2020): 1-14.[4] Peikari, Mohammad, et al. "Automatic cellularity assessment from post-treated breast surgical specimens." Cytometry Part A 91.11 (2017): 1078-1087.

Citation Format: Ali Foroughi Pour, Te-Chia Wu, Jan Martinek, Swarup Kumar, Tobias Anzeneder, Stephanie Torkler, Franziska Sommermeyer, Karolina Palucka, Jeffrey Chuang. Deep learning identifies morphological changes in whole slide images of treatment-resistant TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-01.
Abstract P1-08-23: Androgen receptor as predictive marker for pathologic complete response in breast cancer with neoadjuvant chemotherapy
Authors: Lee Eun-Gyeong , Lee Dong-Eun , Han Jai Hong , Lee Seeyoun , Kang Han-Sung , Lee Eun Sook , Kwon Youngmee , Kim Hyun Hee , Chae Hee Jung , Sim Sung Hoon , Lee Keun Seok , Jung So-Youn
Published: March 2022

Background: Androgen receptors (AR) has emerged as a prognostic factor predicting survival and recurrence in breast cancer. However, the role of AR as a predictor of pathological complete response (pCR) rate after neoadjuvant chemotherapy by subtypes is unclear. This study aimed to investigate according to AR in breast cancer patients undergoing neoadjuvant chemotherapy as a predictor. Furthermore, we estimated the relationship between AR expression and clinicopathological factors. Method: We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center from April 2016 to October 2019. We retrospectively collected the medial records that the clinicopathologic information and AR expression analyzed according to cancer stage, hormonal receptor status, HER2 status, tumor subtype, pCR. Results: Among the 624 breast cancer patients, 529 (84.8%) were AR positive patients and 95 (15.2%) were AR negative patients. The mean age of the patients was 50.0 years. The rate of pCR was 31.4% (196/624). AR negative patients had significantly high rate of pCR than AR positive patients. (AR (-) 43.2% vs. AR (+) 29.3%, p = 0.0074). AR positive patients showed more ER positivity, PR positivity, HER2 positivity and luminal A subtype. A higher proportion of AR positive patients compared to AR negative patients received target therapy and hormonal therapy (target therapy, AR (-) 15.8% vs. AR (+) 43.9%, hormonal therapy, 14.7% vs. 71.0%, p <.0001). The tumor factors associated with pCR were early stage, histologic grade 3, ER negativity, PR negativity, AR positivity, HER2 positivity, and high ki-67%. According to subtypes of tumor, the correlation between AR expression and pCR was. significantly higher in AR negative luminal A type (AR (-) 28.57% vs. AR (+) 7.26%, p =0.0215). The other subtypes did not show a statistically significant difference. Conclusion: This study shows that AR expression is predominant in luminal A subtype. When determining neoadjuvant chemotherapy in luminal A subtype, AR expression can be considered as a pCR predictive marker.

Citation Format: Eun-Gyeong Lee, Dong-Eun Lee, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, Eun Sook Lee, Youngmee Kwon, Hyun Hee Kim, Hee Jung Chae, Sung Hoon Sim, Keun Seok Lee, So-Youn Jung. Androgen receptor as predictive marker for pathologic complete response in breast cancer with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-23.
Abstract P1-10-06: Effect of aging and mTOR inhibition on human mammary stem cells and early breast cancer progression markers
Authors: Broome Larry E , Bouamar Hakim , Lathrop Kate , Jatoi Ismail , Brenner Andrew , Garcia Michael , Nazarullah Alia , Moncada Karla , Kaklamani Virginia , Sun Lu-Zhe
Published: March 2022

Ductal carcinoma in situ (DCIS) is the most common form of breast cancer and is a predecessor to invasive carcinoma development. The origins for early breast cancer have been attributed to aberrant single cells, which may include adult stem and progenitor cells. We performed a window trial with mTOR inhibitor sirolimus in patients with atypical ductal hyperplasia (ADH) or DCIS and investigated the epithelial populations in adjacent normal and ADH/DCIS breast tissues along with their residing stem and progenitor cell activity. Differences associated with age, menopausal status, and treatment by sirolimus have also been explored. While the mammary epithelial populations were seen to be unchanged in aging, we found that age correlates with a decline in stem cell activity. mTOR inhibition was also able to abrogate mammary stem cell activity and decrease luminal progenitor passaging lifespan, particularly in postmenopausal patients. While mTOR inhibition had no effect on myoepithelial populations, it did decrease premenopausal luminal cell populations and reduced prognostic markers associated with breast cancer progression from DCIS to invasive breast cancer. These markers include p16INK4A, COX-2, and Ki67, which were reduced in DCIS breast tissue from patients administered with sirolimus as shown through quantitative analysis of immunohistochemistry. Overall, these findings indicate a link from mTOR signaling to mammary stem cell activity and cancer progression. mTOR inhibitors may have potential for breast cancer prevention.

Citation Format: Larry E Broome, Hakim Bouamar, Kate Lathrop, Ismail Jatoi, Andrew Brenner, Michael Garcia, Alia Nazarullah, Karla Moncada, Virginia Kaklamani, Lu-Zhe Sun. Effect of aging and mTOR inhibition on human mammary stem cells and early breast cancer progression markers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-06.
Abstract P1-12-01: Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial
Authors: Zagouri Flora , Koliou Georgia-Angeliki , Dimitrakopoulos Foteinos , Papadimitriou Christos , Binas Ioannis , Koutras Angelos , Papakostas Pavlos , Markopoulos Christos , Venizelos Vasileios , Xepapadakis Grigorios , Karanikiotis Charisios , Psyrri Amanda , Bafaloukos Dimitrios , Kosmidis Paris , Aravantinos Gerasimos , Res Eleni , Mauri Davide , Koumarianou Anna , Petraki Kalliopi , Tsipoura Anna , Pectasides Dimitrios , Gogas Helen , Fountzilas George
Published: March 2022

Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033

Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-12-01.
Abstract P1-13-02: Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer
Authors: Finnegan Ryan Michael
Published: March 2022

While anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer, relapse after remission continues to be a serious limitation to the effectiveness of these therapies. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into a state of autophagy/senescence from which a subpopulation ultimately escapes, potentially contributing to disease recurrence. ER+ MCF-7 breast tumor cells that were induced into autophagy/senescence by Fulvestrant + Palbociclib in vitro were exposed to the autophagy inhibitors, chloroquine and bafilomycin, prior to as well as after growth arrest. However, autophagy inhibition only moderately enhanced the response to therapy and, at best, delayed proliferative recovery. These findings were confirmed by genetic inhibition of autophagy. Despite clear entry into a state of senescence, the Bcl-xl inhibitor and senolytic ABT-263 (navitoclax) failed to promote tumor cell death; this is likely a consequence of high levels of survivin in the MCF-7 breast tumor cell line. However, the BET inhibitor, ARV-825, eliminated a large fraction of the senescent cell population and significantly delayed proliferative recovery. Cell death did not appear to be a consequence of increased apoptosis. Additionally, analysis of three database sets demonstrated that higher breast cancer expression of BRD4, a primary target of ARV-825, correlated with lower recurrence-free survival compared to patients with cancers expressing lower levels of BRD4. These studies indicate that administration of BET inhibitors, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients by prolonging progression-free survival.

Citation Format: Ryan Michael Finnegan. Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-02.
Abstract P1-24-04: Spatially resolved cell type heterogeneity uncovers the distinct biology of inflammatory breast cancer
Authors: Courtois Elise , Flynn William , Sivajothi Santhosh , Seignon Martine , Luo Diane , Lim Bora , Robson Paul
Published: March 2022

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer due to rapid progression, distinct morbidity due to pain, swelling, infection and eventual death. It accounts for 10% of all breast cancer caused deaths despite being only 2-4% of all breast cancer diagnosis. Histopathologically, scattered tumor emboli and dermal lymphatic invasion are typical histopathological findings of IBC, shown in about 75% of all IBC cases. However, the etiology of this disease remains largely unknown and its diagnostic difficult to establish.Using single cell transcriptomics, we profiled a total of 10 patient-derived needle biopsies from IBC-hormone receptor (IBC-HR), IBC-triple negative breast cancer (IBC-TNBC), TNBC and HR subtypes, and one normal breast sample. After data QC, we obtained a total of 36,000 cells representing immune, epithelial and stromal cell populations. We performed analysis of the spatial cell distribution through a transcriptomics-informed panel using highly multiplex imaging mass cytometry (IMC) on FFPE section obtained from the same patients.While we noted interpatient heterogeneity within cancer cells in our single cell dataset, immune and stromal cells did show similarity across IBC patients. We identified differences across the myeloid compartment between IBC and non-IBC cells, specifically affecting the dendritic cell subpopulations.The interferon gamma pathway was specifically elevated in several cell types across IBC patients, and particularly in immune cells such as T and myeloid cells. We used MX1 as a marker of interferon gamma response as part of the IMC panel and confirmed this signature in IBC samples. There was no alpha and beta interferon transcriptomic signature in the single cells. Through IMC, we were able to identify the cellular composition surrounding the tumor microemboli. Contrary to what has been postulated in the literature, these cells are not lymphatic cells, but appear to be of fibroblastic origin and express the fibroblast marker CD90. As well, we detected a non-overlapping distribution of Collagen 1 positive and CD90 positive fibroblasts throughout the IBC specimens, revealing heterogeneity within the fibroblast population and its organization. Spatial immune cell analysis also revealed the presence of tertiary lymphoid structures in IBC tumors.

Citation Format: Elise Courtois, William Flynn, Santhosh Sivajothi, Martine Seignon, Diane Luo, Bora Lim, Paul Robson. Spatially resolved cell type heterogeneity uncovers the distinct biology of inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-04.
Abstract P2-08-01: Validation of a 16-gene genomic signature to identify early-stage invasive breast cancer patients who may omit radiotherapy
Authors: Fyles Anthony , Chang S. Laura , Rey-McIntyre Katrina , Shi Wei , Feng Felix , Speers Corey , Pierce Lori , McCready David , Liu Fei-Fei
Published: March 2022

Background While whole breast radiotherapy has been standard of care for invasive breast cancer patients treated with breast conserving surgery, not all women may benefit from radiotherapy. Recently, we demonstrated that a 16-gene signature named Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) could identify breast cancer patients with HR+, HER2- tumors treated with breast conserving surgery alone with a 10-year locoregional recurrence risk of less than 10%. Methods In this study, we apply the signature to patients enrolled in the Princess Margaret Trial, a randomized trial where patients age 50 years or older were randomized to radiotherapy and tamoxifen or tamoxifen alone after breast conserving surgery. Tissue from 132 patients with HR+, HER2- tumors were available for gene expression analysis. Results For women treated with tamoxifen alone after breast conserving surgery, POLAR identified low risk women with a 7% risk of locoregional recurrence at 10 years. Comparison to POLAR-low patients treated with adjuvant radiotherapy did not demonstrate a significant benefit from radiotherapy (HR=1.5[0.14-16], p=0.74). POLAR-high patients not treated with radiotherapy had a 22% risk of locoregional recurrence at 10 years. Comparison to POLAR-high patients treated with adjuvant radiotherapy demonstrated a significant benefit from standard radiotherapy (HR=0.25[0.07-0.92], p=0.038). Conclusions These data suggest that the POLAR genomic signature may be used to identify patients with a low risk of locoregional recurrence without significant benefit from adjuvant radiotherapy. Patients with low POLAR scores may potentially be candidates for radiation therapy omission when treated with breast conserving surgery and tamoxifen.

Citation Format: Anthony Fyles, S. Laura Chang, Katrina Rey-McIntyre, Wei Shi, Felix Feng, Corey Speers, Lori Pierce, David McCready, Fei-Fei Liu. Validation of a 16-gene genomic signature to identify early-stage invasive breast cancer patients who may omit radiotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-01.
Abstract P2-10-07: Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy
Authors: Lee Young Joo , Noh Woo C , Nam Seok J , Park Byeong-Woo , Lee Eun S , Im Seock A , Jung Yong S , Yoon Jung H , Kang Sung S , Park Kyong H , Lee Soo-Jung , Lee Min H , Jeong Joon , Kim Sung Y , Kim Hyun-Ah , Han Se-Hwan , Han Wonshik , Hur Min H , Kim Seonok , Ahn Sei-hyun , Kim Hee J
Published: March 2022

Introduction Addition of ovarian function suppression to conventional endocrine therapy alone in premenopausal women provides a survival benefit with moderate to high risk hormone-receptor positive breast cancer, especially who received chemotherapy Prediction of menstruation recovery after chemotherapy is important for deciding subsequent endocrine treatment and addressing fertility issues. Methods In the adding OFS after chemotherapy trial (ASTRRA), patients who resumed ovarian function up to 2 years after chemotherapy were randomized to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. With these 1383 patients, we developed a model that predicts when patients recover menstruation within 3 years after chemotherapy using several variables including age, BMI, chemotherapy regimen and duration, serum E2 and FSH level. Results A total of 1017 patients data were used to develop prediction model and 366 patients data were used for external validation. In development group, 546 (53.6%) patients resumed menstruation during follow up period of 5 years. In multivariable analysis, younger age and AC based regimen without taxane were strong predictive factor for menstruation recovery. However predictive value of chemotherapy regimen was not constant over time. Therefore, we conducted another model with patients (n= 624) who did not recover menstruation within one year. In this patient group, predictive factors for menstruation recovery was age and serum E2 level at 6 months after chemotherapy. We also conducted a simplified scoring system to estimate change of recovery by using risk factors mentioned above. Conclusion Younger age is an important persisting factor predicting menstrual recovery after chemotherapy. Although chemotherapy regimen predicts shor-term menstrual recovery, over time, patient factors have more predictive influence on recovery. Recovery of serum E2 level would be important to predict subsequent menstruation recovery.

Citation Format: Young Joo Lee, Woo C Noh, Seok J Nam, Byeong-Woo Park, Eun S Lee, Seock A Im, Yong S Jung, Jung H Yoon, Sung S Kang, Kyong H Park, Soo-Jung Lee, Min H Lee, Joon Jeong, Sung Y Kim, Hyun-Ah Kim, Se-Hwan Han, Wonshik Han, Min H Hur, Seonok Kim, Sei-hyun Ahn, Hee J Kim. Prediction of menstruation recovery timing in premenopausal breast cancer patients taking tamoxifen after chemotherapy: An ASTRRA substudy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-07.
Abstract P2-12-16: Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis
Authors: Lee Young Joo , Kim Seonok , Kim Hee J
Published: March 2022

Backgrounds Ovarian function suppression by gonadotropin releasing hormone agonist (GnRHa) is used to preserve fertility during neoadjuvant chemotherapy (NCT) in breast cancer especially in young women. Some results showed that patients with hormone-receptor (HR) negative breast cancer treated with NCT concurrent with GnRHa to preserve fertility had better outcome than without GnRHa. Methods From 2011 to 2014, 296 women aged under 40 years old with stage I to IIIA breast cancer, treated with NCT before surgery were analyzed. Primary endpoint was rate of pathologic complete response (pCR). Secondary endpoint was disease free survival (DFS) and overall survival (OS) between two groups categorized by concurrent with GnRHa during NCT to preserve fertility. Subgroup analysis was done with different HR status. Results Ninety-eight patients (33.1%) received concurrent GnRHa with NCT. Baseline characteristic showed no different between two groups except younger age with GnRHa group (p<0.001) and more use of GnRHa in HR+/HER2- subtype (p=0.023). pCR rate was higher with GnRHa group (8.08% vs 20.41%, p=0.002). However there was no significant difference in 5yr DFS between without GnRHa and with GnRHa (HR 1.4 95% CI 0.60 2-3.582) in entire cohort. In HR positive subcohort, 5yr DFS was not different between without GnRHa and with GnRH a group (80.9% and 87.7% respectively,p=0.643). In HR negative subcohort, 5yr DFS was 71.6% vs 70.6% (p=0.931). There were no overall survival difference between two group in entire and subcohort (p>0.05). Multivariable analysis also did not show survival improvement after use of GnRHa in HR- subtype (hazard ratio 2.166, (95% CI 0.746-6.292), p=0.155) and HR+ subtype (hazard ratio 1.231, (95% CI 0.205-7.411), p=0.820). Conclusion Among young women with breast cancer with negative hormone receptor treated with concomitant GnRHa achieved more pCR com compared with no GnRHa during chemotherapy. This result did not reach out to better survival outcome at this point. Trend to better outcome seen in survival curve implies further evaluation in this particular population.

Citation Format: Young Joo Lee, Seonok Kim, Hee J Kim. Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-16.
Abstract P3-01-13: Comparing portable and clinical ultrasound systems using 3D printed breast phantom inserts
Authors: Valdez Dustin , Fukui Jami , Wolfgruber Thomas , Leong Lambert , Maskarinec Gertraud , Shepherd John
Published: March 2022

Background: Late-stage breast cancer rates in the Pacific where mammography services are limited are exceedingly high. Therefore, alternative accessible breast cancer screening technologies such as portable ultrasound is needed. However, little is known about the performance of portable ultrasound when compared to clinical ultrasound for use in breast cancer screening. By utilizing 3D printing technology, it is possible to design breast phantom inserts to replicate various types of lesions. In this study, we utilized 3D printed breast phantom inserts to compare portable and clinical ultrasound lesion detection performance. Methods: Four different breast inserts were designed using FreeCAD (version 0.19) to replicate different lesion detection properties. The first insert compares lesion shape, the second insert investigates depth and size, the third insert looks at fiber diameter, and the fourth insert looks at clusters. The four inserts were printed using a photopolymer resign (Formlabs Inc Rigid resign, Somerville, MA, USA) and then placed in a gelatin-based breast phantom designed for ultrasound use. Using the portable ultrasound (GE Vscan Extend) and clinical ultrasound (Philips EPIQ 5G), various images were captured of identical angle and orientation for both devices. The number of lesions visualized were counted and presented as a percentage of lesions detected. Results: The portable ultrasound had a 100% lesion detection rate for breast insert 1, 90.3% for breast insert 2, 70% for breast insert 3 and 55.8% for breast insert 4. Clinical ultrasound had 100% lesion detection rate for breast insert 1, 93.1% for breast insert 2, 76.6% for breast insert 3, and 99% for breast insert 4. Conclusion: Portable ultrasound shows comparable lesion detection capabilities to clinical ultrasound in 3 of the 4 breast phantom insert tests. Portable ultrasound may have potential as a capable accessible breast cancer screening device in areas without mammography.

Citation Format: Dustin Valdez, Jami Fukui, Thomas Wolfgruber, Lambert Leong, Gertraud Maskarinec, John Shepherd. Comparing portable and clinical ultrasound systems using 3D printed breast phantom inserts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-13.
Abstract P3-03-22: Use of 64Cu-DOTA trastuzumab positron emission tomography to predict pathologic complete response in locally advanced HER2 positive breast cancer
Authors: Mortimer Joanne , Rockne Russell , Liu Jessica , Yuan Yuan , Stewart Daphne , Waisman James , Frankel Paul , Kruper Laura , Adhikarla Vikram
Published: March 2022

Use of 64Cu-DOTA trastuzumab Positron Emission Tomography to predict pathologic complete response in locally advanced HER2 positive breast cancer. Background: We have demonstrated that 64Cu-DOTA trastuzumab is an effective PET imaging agent of HER2 positive breast cancer and correlated with HER2 status by IHC. Methods: Patients with locally advanced breast cancer were eligible if they had biopsy confirmed HER2 + disease, locally advanced disease and were to be treated with neoadjuvant therapy. Pretreatment staging included a breast MRI, 18F-FDG-PET/CT and 64Cu-trastuzumab-PET/CT (64CuT-PET). Prior to injection of 64Cu-trastuzumab, patients received 50 mg of cold trastuzumab per our previously established protocol. 64CuT-PET was obtained at 21-25 h over fields of view chosen in reference to MRI. Uptake in lesions was measured in terms of body wt-normalized SUV. Lesions with intensity > adjacent tissue were considered positive on PET. Breast MRI was obtained after 4 cycles of chemotherapy and preoperatively. Response to therapy was determined on the surgical specimen. Results: Eighteen women have completed study and are evaluable for treatment response. The median age was 56 years (Range 32-62); 5 were ER- and PR-; 13 ER+/- PR+. One patient had increased 64CuT-PET uptake at T4 which was not appreciated on conventional imaging and subsequent biopsy confirmed metastatic disease. She is included in the analysis as she ultimately underwent surgical management of the breast. Complete pathologic response was seen in 14/18 patients - 11/14 ER+/- PR + and 3/4 ER-/PR-. Four patient had residual disease at surgery; 3 of 4 were HER2 negative and 1 was HER2+. Uptake on 64CuT-PET correlated with increased uptake on 18F-FDG-PET. The ratio of 64CuT-PET: 18F-FDG-PET ≥ 0.7 was associated with complete pathologic response at surgery.Conclusions: The ratio of 64CuT-PET to 18F-FDG-PET ≥ 0.7 was associated with complete pathologic response in women undergoing neoadjuvant chemotherapy for locally advanced HER2+ breast cancer. Residual disease after HER2-directed therapy was frequently HER2 negative.

Citation Format: Joanne Mortimer, Russell Rockne, Jessica Liu, Yuan Yuan, Daphne Stewart, James Waisman, Paul Frankel, Laura Kruper, Vikram Adhikarla. Use of 64Cu-DOTA trastuzumab positron emission tomography to predict pathologic complete response in locally advanced HER2 positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-22.