bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES9-2: Special indications where local therapy should be considered
Authors: Lucci A
Published: March 2022

Clarity for the clinical issue of which patients with metastatic breast cancer should undergo local/regional therapy (LRT) was provided by the recent presentation of the prospective randomized ECOG-ACRIN 2108 trial data. This study, which randomized Stage IV breast cancer patients (initially treated with optimal systemic therapy for 4-8 months) to early local therapy or to continued systemic therapy alone, failed to demonstrate an improvement in overall survival for patients who had early local therapy compared to continued systemic therapy alone. However, there are some special indications that fall outside of this trial, and which remain areas of controversy. For instance, the subset of patients with inflammatory breast cancer (IBC) were not included in the ECOG trial, and therefore there are no prospective randomized clinical trial data available to determine if LRT improves survival in de novo stage IV IBC patients. To further confound the issue, several retrospective studies show clear survival benefit for Stage IV IBC patients who complete LRT, versus those who do not. While we all recognize that some differences could be attributed to selection bias, the differences in outcome are so striking that we believe that it warrants further discussion of the possible value of LRT in the IBC group. Furthermore, patients with IBC are more likely to be found to have Stage IV disease at presentation, complicating the discussion of whether complete trimodal therapy (neoadjuvant chemotherapy, mastectomy, and post-mastectomy radiation therapy) should still be considered at initial treatment planning, or whether LRT should be omitted altogether. Finally, due to the skin involvement and rapid progression inherent to IBC, these patients often require LRT for palliation of advanced disease (to control fungating tumors, brachial plexus involvement, etc.), so palliative surgery plays an important role in the management of the patient with IBC. During this presentation, we plan to discuss the available data regarding optimal LRT decisions for patients with de novo Stage IV IBC. Beyond the subset of IBC patients, several studies have identified non-IBC patients with Stage IV disease who might benefit from LRT. We will also discuss subsets of Stage IV breast cancer patients, including those with HR+ tumors, those with bone-only oligometastasis, and younger age patients, where LRT has shown survival benefit, based mainly on longer follow-up data from the randomized MF07-01 trial. Our objective is to improve knowledge of the local/regional treatment recommendations of select subgroups of Stage IV patients, where the use of LRT could translate to not only improved local control, but possibly to improved survival in carefully selected patients.

Citation Format: A Lucci. Special indications where local therapy should be considered [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 ES9-2.
Abstract ES9-3: Oligo-progressive disease. Treating locally more than systemically
Authors: Xu A
Published: March 2022

Advances in cancer therapies and technologies have shifted the paradigm for treating metastatic disease. Patients with stage IV disease are living longer and technologic advances enable us to deliver local therapies, such as surgical resection, radiofrequency ablation, or stereotactic radiosurgery, with lower toxicities. Genetic deep sequencing has helped us understand metastases to be genetically heterogeneous with independent subpopulations evolving in response to environmental pressures. We currently understand metastatic progression from primary tumor to disseminated disease to involve multiple stages, raising the possibility of an intermediate, curable, oligometastatic state with limited metastatic potential. The clinical relevance of oligometastases has been validated in multiple, recent randomized clinical trials. Metastasis directed therapies have been demonstrated to improve overall survival, however, this benefit is not seen in all patients, and breast specific data are lacking. This educational presentation will review randomized evidence supporting local treatment of oligometastases. We will also review evidence specific to breast cancer and highlight the critical need to define when local therapies can be effective at disrupting metastatic progression in breast cancer patients.

Citation Format: A Xu. Oligo-progressive disease. Treating locally more than systemically [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 ES9-3.
Abstract P1-05-06: Establishment of novel BRCA1ness score to quantify BRCAness in breast cancer
Authors: Oshi Masanori , Wu Rongrong , Yamada Akimitsu , Yan Li , Ishikawa Takashi , Endo Itaru , Takabe Kazuaki
Published: March 2022

Germline mutations in the loci of BRCA1 or BRCA2 genes with loss of heterozygosity or additional somatic truncation at the WT allele in breast cancer result in characteristic clinicopathological features of homologous recombination deficiency, also known as “BRCAness.”. Although clinical genetic testing for mutations of BRCA1 and BRCA2 has increased the chances of identifying pathogenic variants, we speculated that there may be a difference in cancer biology by the degree of BRCAness. To address this question, we sought to develop a means to estimate the amount of BRCAness using a score consists of BRCA1-mutation-related genes. Thirty-four BRCA1-mutation related genes were selected by high area under the curve (AUC) levels in receiver operating characteristic (ROC) curve between BRCA1 mutation and non-mutation breast cancer, consistently in two large breast cancer cohorts, TCGA and METABRIC. The score was established by using gene set variation analysis (GSVA) algorithm on 34 genes. We found that the BRCA1ness score was the highest in triple negative breast cancer (TNBC) among subtypes consistently in both cohorts (both p < 0.001). Although BRCA1ness score did not correlate with mRNA expression of BRCA1 nor BRCA2 at all (spearman’s rank correlation coefficient (r) = 0.191 and 0.093, respectively), high BRCA1ness score was significantly associated with high rate of BRCA1 mutation (AUC = 0.735 and 0.709, respectively) in both cohorts. This level of AUC for BRCA1ness mutation score was highest compared to other factors, including BRCA1 expression (AUC = 0.323), DNA repair gene set score (AUC = 0.553 and 0.543), nor homologous recombination deficient (HRD) (AUC = 0.659), which are known as the characteristics of BRCAness. Furthermore, the score was significantly correlated with DNA repair gene set score (r = 0.593 and 0.323, both p < 0.01) as well as MKI67 expression (r = 0.655 and 0.626, both p < 0.01) in both cohorts. HRD score was also strongly correlated with BRCA1ness score in the TCGA cohort (r = 0.633). Interestingly, high BRCA1ness was significantly associated with worse disease-free survival (DFS) (p = 0.037 and p < 0.001, respectively) and disease-specific survival (DSS) (p = 0.012 and p < 0.001, respectively) in both cohorts. In conclusion, we established novel BRCA1ness score using mRNA expression of BRCA1-mutation-related genes, and found that it associate with DNA repair and worse survival.

Citation Format: Masanori Oshi, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Establishment of novel BRCA1ness score to quantify BRCAness 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 P1-05-06.
Abstract P1-08-11: Clinical relevance of host immunity in patients with breast cancer who received neoadjuvant chemotherapy
Authors: Bae Soong June , Ji Jung Hwan , Chu Chihhao , Cha Yoon Jin , Kim Jee Hung , Ahn Sung Gwe , Jeong Joon
Published: March 2022

Background Host immunity plays a key role in breast cancer progression. It seems that the neutrophil-to-lymphocyte ratio (NLR) may reflect the systemic host immunity, and tumor-infiltrating lymphocytes (TILs) may reflect the localized host immunity. This study aimed to analyze the clinical relevance of host immunity combining NLR and TILs to treatment efficacy and survival.Methods We assessed the pre-treatment NLR and TILs from core-biopsy samples in 461 patients with breast cancer who received neoadjuvant chemotherapy. The patients were assigned into two groups: the intact host immunity group (NLR < 2.75 and TILs ≥ 30%) and the defective host immunity group (the remainder; NLR > 2.75 or TILs < 30%). We investigated the pathologic complete response (pCR) and recurrence-free survival (RFS) according to host immunity.ResultsOf the total, 141 (30.6%) patients belong to the intact host immunity group, and 320 (69.4%) patients belong to the defective host immunity group. A pCR was achieved in 76 (53.9%) of 141 patients in the intact host immunity group, whereas a pCR was achieved in 96 (30.0%) of 320 patients in the defective host immunity group (P<0.001). The intact host immunity was an independent predictor for high pCR (adjusted odds ratio [OR], 2.65; 95% confidence interval [CI], 1.74-4.03). Furthermore, the Cox proportional hazards regression models revealed that the intact host immunity obtained an independent prognostic value for favorable RFS after adjusted for clinicopathologic factors including pCR (adjusted hazard ratio [HR], 0.33; 95% CI, 0.11-0.98; P=0.045).ConclusionHost immunity based on the combined analysis of NLR and TILs provides information regarding the treatment response and prognosis in patients with breast cancer receiving neoadjuvant chemotherapy. There is a need for a new therapeutic strategy to activate the immune system in patients with defective host immunity. 2

Citation Format: Soong June Bae, Jung Hwan Ji, Chihhao Chu, Yoon Jin Cha, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. Clinical relevance of host immunity in patients with breast cancer who received 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 P1-08-11.
Abstract P1-24-02: Genetic variants and tumor microenvironment in inflammatory breast cancer: Clues for targeted therapies
Authors: Arisi Maria F. , Gong Yulan , Nagarathinam Rajeswari , Gerratana Lorenzo , Pei Jianming , Cai Kathy Q. , Winn Jennifer , Hasse Zachary , Obeid Elias , Noriega Julio , Sebastiano Christopher , Ross Eric , Alpaugh R. Katherine , Cristofanilli Massimo , Fernandez Sandra V
Published: March 2022

Background: Inflammatory breast cancer (IBC) is characterized by a young age at diagnosis, high metastatic potential, and poor overall survival. To better understand the etiology of this aggressive disease, we performed a retrospective study to evaluate genomic alterations and tumor microenvironment in IBC patients. Methods: Targeted next generation sequencing (NGS) was performed using blood cell-free DNA (cfDNA) (n=32), paired DNA from tumor tissues (n=29) and DNA from whole blood or normal tissue (n=20). We also characterized the tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1 and PD-L1) through immunohistochemistry (IHC) staining. Results: Our results shown a high incidence of germline variants in patients with IBC that could be associated with an increased risk of developing the disease. Germline variants were found more frequently in patients with TN (38.9%) than non-TN IBC (28.6%). IHC staining revealed that in 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs. Patients with PD-L1&PD-1 positive biopsies had a lower OS (31 months) than patients with PD-L1&PD-1 negative (38 months) tumors, though the difference was not statistically significant. PD-L1&PD-1 positive tumors had significantly more CD8+ (cytotoxic T-cells), CD20+ (B-cells) and FoxP3+ (Tregs) cells than PD-L1&PD-1 negative ones. Furthermore, most IBC patients showed to have deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. All tumor biopsies showed positive staining for p-FAK1(Tyr 397). Conclusion: A subset of IBC patients (29%) expressed both PD-L1 and PD-1 on tumor immune cells infiltrates, providing rationale for testing PD-1/PD-L1 blocking therapies. IBC patients could have benefits from PD-1/PD-L1 blocking therapies alone or in combination with PARP or FAK (Tyr397) kinase inhibitors, both having the capacity of altering the tumor microenvironment.

Citation Format: Maria F. Arisi, Yulan Gong, Rajeswari Nagarathinam, Lorenzo Gerratana, Jianming Pei, Kathy Q. Cai, Jennifer Winn, Zachary Hasse, Elias Obeid, Julio Noriega, Christopher Sebastiano, Eric Ross, R. Katherine Alpaugh, Massimo Cristofanilli, Sandra V Fernandez. Genetic variants and tumor microenvironment in inflammatory breast cancer: Clues for targeted therapies [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 P1-24-02.
Abstract P2-03-04: Characteristics and clinical differences of breast cancer patients with negative or low HER2 expression
Authors: Voutsadakis Ioannis , Rosso Christopher
Published: March 2022

Background: High expression of HER2 receptor in Immunohistochemistry (IHC) sections or amplification of its gene in in situ hybridization (ISH) assays define a subset of breast cancers that have an aggressive natural history but respond to treatments blocking HER2. In contrast, patients with lower HER2 expression, not meeting the criteria for positivity, are currently treated similarly to completely HER2 negative patients. However, emerging data suggest that patients with low HER2 expression may derive benefit from newer antibody drug conjugates. Thus, this investigation sought to clarify the characteristics of HER2 low expressors and compare them with patients with no HER2 expression. Methods: We undertook a retrospective analysis of all breast cancer patients seen in our cancer center over a six-year period and classified as HER2 negative. Patients were categorized as HER2 negative when they had a score of 0 in IHC and as HER2 low if they had a score of 1+ or 2+ in IHC and no amplification by ISH. Characteristics of the patients and tumors in the two groups were compared. Results: A total of 391 HER2 negative and low patients have been included. Among them, 130 patients (33.2%) were HER2 negative (score 0 by IHC) and 261 patients (66.8%) were HER2 low (score 1+ and 2+ by IHC/ISH non-amplified). There were no differences in age, menopause status, mode of detection of cancer (clinical or screening) and clinical stage at diagnosis between the two groups. Patients in the HER2 low group had less commonly high-grade cancers than HER2 negative patients (25.35 versus 34.6%, x2 p=0.04).In addition, The HER2 low group had higher ER Histoscore (>240) in 88.1% of cases compared with 69.2% in HER2 negative group (x2 p<0.000). Similarly, a higher percentage of HER2 low cases than HER2 negative cases were expressing the progesterone receptor (PR, x2 p<0.000). HER2 low patients were rarely (3.8%) classified as triple negative, while this percentage was 21.5% in HER2 negative patients. Conclusion: HER2 negative staining (IHC score 0) is associated with averse tumor characteristics compared with clinically HER2 negative patients with low HER2 expression (score 1+ and 2+/ISH non-amplified).

Citation Format: Ioannis Voutsadakis, Christopher Rosso. Characteristics and clinical differences of breast cancer patients with negative or low HER2 expression [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 P2-03-04.
Abstract P2-04-01: Overexpressed cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors
Authors: Liu Qiang , Cai Zijie , Wang Jingru , Li Yudong , Wong Lok Lam
Published: March 2022

CDK4/6 inhibitors are now the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable, limiting its use and efficacy. The mechanisms and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells express significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 directly led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib in palbociclib-resistant cells. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib in resistant cells both in vitro and in vivo. The tumors from breast cancer patients who progressed after palbociclib treatment had significantly higher protein expression of Cyclin D1, CDK4, p-AKT and p-4E-BP1 than the paired samples before palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

Citation Format: Qiang Liu, Zijie Cai, Jingru Wang, Yudong Li, Lok Lam Wong. Overexpressed cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors [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 P2-04-01.
Abstract P2-11-14: Pathology AI features and immune biomarkers of postpartum involution: Implications for postpartum breast cancer
Authors: Ogony Joshua Were , De Bel Thomas , Radisky Derek , VanderLaak Jeroen , Sherman Mark
Published: March 2022

Breast cancer risk is increased in parous women in the period following childbirth, peaking at five years. After weaning or in the absence of lactation, the breast undergoes postpartum involution (PPI), a process characterized by epithelial cell death and tissue remodeling that returns the mammary gland to a baseline state, and has previously been associated with increased inflammation and breast cancer development and progression in preclinical models. Features of PPI and determinants of related inflammation have been incompletely characterized among women. In this study, we performed visual and AI analysis of 725 digitized H&E images of normal breast tissues donated to the Komen Tissue Bank (KTB) by parous and nulliparous women ≤45 years, and further investigated the immune microenvironment in specimens from 23 women (also from KTB, 13 parous, 10 nulliparous) using NanoString RNA immuno oncology (IO) 360 panels and immune protein biomarkers by NanoString GeoMx Digital Spatial Profiling (DSP). We found that recently parous women (≤5 years of a last birth) had higher numbers of terminal duct lobular units (TDLUs), immune cells, and plasma cells as compared with nulliparous women, and that beyond 5 years of a last birth, TDLU numbers were still higher in parous women, but the immune and plasma cell content of the breast of parous and nulliparous women were not significantly different. Our gene expression analysis revealed differential expression of genes that clustered according to parity status, with interferon stimulated genes; STAT1 and IFITM1, and interferon alpha receptor 1 (IFNAR1), and MHC class II genes (HLA-DMA, HLA-DPA,HLA-DPB1, and HLA-DRA) elevated in parous women. Our DSP analysis revealed that immune biomarkers with immunosuppressive functions, including ARG1, VISTA, CTLA-4, and CD68 were significantly higher in parous women as compared with nulliparous women. Breast tissues of parous women show lobular expansion and alterations in immune cell components compared with nulliparous tissues. Further research is needed to assess how these alterations may impact risk.

Citation Format: Joshua Were Ogony, Thomas De Bel, Derek Radisky, Jeroen VanderLaak, Mark Sherman. Pathology AI features and immune biomarkers of postpartum involution: Implications for postpartum 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 P2-11-14.
Abstract P2-12-19: Platinum is essential in neoadjuvant treatment of triple negative breast cancer: A network meta-analysis
Authors: Li Junjie , Chen Li , Tan Wei , Qi Fang , Zhang Yang , Wang Zhonghua , Shao Zhimin
Published: March 2022

Background: Due to the heterogeneity of triple negative breast cancer (TNBC) and variety of neoadjuvant regimen, the best way to provide optimal neoadjuvant regimen in early-stage TNBC is still a challenge. However, the preferred regimen, especially when combining target therapy such as bevacizumab, Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi), and PD-1/PD-L1 inhibitor, is still not clear. Methods: Medline, EMBASE, Cochrane Library, and Web of Science were searched in May 2020 to identify randomized controlled trials (RCTs). We conducted a fixed-effect network meta-analysis (NMA) with a Bayesian framework to assess the efficacy and safety of different neoadjuvant regimens for patients with early or locally advanced TNBC. (Registration: PROSPERO CRD42020223012). Results: A total of 35 RCTs involving 8424 participants were included, of which, 22 RCTs with 5203 patients were included in this NMA focusing on pathologic complete response (pCR). Compared to anthracycline-taxane based regimen (AT), an improvement in pCR was observed for anthracycline-taxane based combined platinum (ATP) (odds ratio [OR]=2.04, 95% credible interval [CrI]: 1.69, 2.48), TCb (T= docetaxel; Cb= carboplatin; OR=2.16, 95%CrI: 1.20, 3.91). Combining target therapy (including bevacizumab [Bev], veliparib, atezolizumab, or pembrolizumab) with AT or ATP also improved pCRs. Eleven RCTs reported serious adverse events (SAEs), and five RCTs were included in NMA. TCb was associated with less serious adverse events than AT. However, ATP, AT+Bev, ATP+Bev, ATP+Veliparib and ATP+Pembro were associated with more serious AEs than AT. Conclusions: Platinum-based neoadjuvant regimens increased pCRs in TNBC patients, among which TCb was preferred with less SAEs. Platinum-based regimens should also be considered a preferred option when combining target therapy such as Bev, PARPi, and PD-1/PD-L1 inhibitor.

Citation Format: Junjie Li, Li Chen, Wei Tan, Fang Qi, Yang Zhang, Zhonghua Wang, Zhimin Shao. Platinum is essential in neoadjuvant treatment of triple negative breast cancer: A network meta-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 P2-12-19.
Abstract P2-13-37: A prospective, open, multi-center clinical study of pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvant treatment for stage II-III HER2-positive breast cancer patients
Authors: Shao Bin , Yu Zhengyan , Wang Yu , Zhao Guangcai , Zhou Fei , Wei Ranmei
Published: March 2022

Background: Targeted therapy has significant efficacy in adjuvant and advanced treatment of HER2-positive breast cancer, and it has also promoted its development in neoadjuvant therapy. For HER2-positive breast cancer, chemotherapy with anthracyclines and taxanes combined with trastuzumab targeted therapy is currently the standard regimen for adjuvant or neoadjuvant therapy. On the basis of the preliminary clinical trials, we carried out this study to confirmed efficacy and safety of pyrotinib combined with trastuzumab and nab-paclitaxel as neoadjuvant treatment regimen in patients(pts) with stage II- III HER2-positive breast cancer. Method: In this multicenter, single arm, prospective, open-label phase II study, 46pts with stage II-III HER2-positive breast cancer will be enrolled (in Simon twostages model, 16 pts will be enrolled in the first stage) to receive pyrotinibcombined with trastuzumab and nab-paclitaxel. The inclusion criteria are asflows. (1) female aging from 18 to 75; (2) Eastern Cooperative Oncology Group(ECOG) performance score of 0-1; (3) Life expectancy is no less than 12weeks;(4) Pathologically confirmed HER-2 positive breast cancer;(5) earlystage (T2-3, N0-1, M0) or locally advanced (T2-4, N2, or N3), with tumor sizeno less than 2cm in diameter. All pts will receive pyrotinib (400mg qd) andtrastuzumab: 8 mg/kg for cycle 1 and 6 mg/kg for cycles 2-6, intravenousinfusion, 21 days for 1 cycle, a total of 6 cycles and nab-paclitaxel: 260mg/m2,intravenous infusion, 21 days as a cycle, a total of 6 cycles. The primaryendpoint is pathological complete response rate (pCR: ypT0/is, ypN0), and thesecondary endpoints are disease-free survival time (DFS), objective responserate (ORR), and survival time without distant metastasis (DDFS). Findings: From Nov 2020 to May 2021, a total of 11 pts were enrolled, 4 pts havecompleted surgery and 6 pts could be evaluated for ORR. The pCR rate was50%, ORR was 100% (5 PR, 1CR). Adverse events (AEs) of any garde werediarrhea 11 (100.0%), anorexia and vomiting 8 (72.7%) and rash 4 (36.4%).Garde 3 AEs were diarrhea 3 (27.3%), and there was no grade 4 AEs. Conclusion: Pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvanttreatment for pts with stage II-III HER2-positive breast cancer showedacceptable toxicity and promising efficacy.

Citation Format: Bin Shao, Zhengyan Yu, Yu Wang, Guangcai Zhao, Fei Zhou, Ranmei Wei. A prospective, open, multi-center clinical study of pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvant treatment for stage II-III HER2-positive breast cancer patients [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 P2-13-37.
Abstract P3-01-09: Mri in the pre-operative workup of breast cancer patients
Authors: Bayard Solange , Fasano Genevieve , Chen Yalei , Marti Jennifer , Simmons Rache , Swistel Alexander , Drotman Michelle , Davis Melissa , Newman Lisa
Published: March 2022

PurposeThe utility of pre-operative MRI (preop MRI) for patients with a new breast cancer diagnosis is controversial. Recently there has been increased use of routine MRI during preoperative workup to evaluate for areas necessitating additional biopsy and planning of operative resection extent; however, these practices carry the risk of delaying treatment, and subjecting patients to unnecessary biopsies and overly extensive resections. Triple negative breast cancer (TNBC) is more difficult to detect on mammography compared to non-TNBC, and patients with TNBC do not receive the chemoprevention benefits of adjuvant endocrine therapy; preop breast MRI to detect mammographically occult foci of disease may therefore be more relevant for patients with TNBC. MethodsOutcomes were evaluated for TNBC patients treated in the prospectively-maintained database of an academic cancer program in a metropolitan city of the Northeast, 1998-2018. ResultsOf 428 TNBC cases, 35.7% (153) had pre-op MRI. 43.6% (61) of 140 TNBC cases ≤50 years old had pre-op MRI compared to 31.9% of 288 TNBC cases >50 years old (p=0.016). There were no differences in race, or stage at presentation between those who had pre-op MRI and those who did not. 34% (52) of pre-op MRI TNBC cases underwent additional biopsies versus 0.43% (1) of TNBC patients who did not have pre-op MRI (p<0.0001). Average time to treatment was 29.5 days for pre-op MRI TNBC cases compared to 25 days for TNBC patients who did not have pre-op MRI (p=0.0026). 9.8% (15) of pre-op MRI TNBC cases underwent re-excisions versus 17.7% (41) of TNBC patients who did not have pre-op MRI (p=0.076). Of those who had mastectomies, patients who had pre-op MRI were more likely to have bilateral mastectomies (21.6% (33) pre-op MRI TNBC v 12.9% (30) of TNBC patients who did not have pre-op MRI (p=0.0471)). Five-year overall survival was no different between patients who had pre-op MRI and those who did not (95.2% vs 95.3% respectively; p=0.79). Among patients undergoing breast conserving surgery, there were no significant differences in the rates of local recurrence between patients that had preop MRI compared to those that did not (13.1% vs 9.1% p=0.392). ConclusionOur data demonstrated that preop MRI in TNBC patients was associated with additional biopsies, more extensive breast surgery, and longer time to treatment. Preop MRI had no impact on survival or local recurrence among patients undergoing breast conserving surgery.

Citation Format: Solange Bayard, Genevieve Fasano, Yalei Chen, Jennifer Marti, Rache Simmons, Alexander Swistel, Michelle Drotman, Melissa Davis, Lisa Newman. Mri in the pre-operative workup of breast cancer patients [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 P3-01-09.
Abstract P3-01-14: A model incorporating axillary tail position on mammography for preoperative prediction of non-sentinel lymph node metastasis in patients with initial cN+ breast cancer after neoadjuvant chemotherapy
Authors: Wang Kun , Zhu Teng , Zhang Tingfeng
Published: March 2022

Background and Objectives: Few models with good discriminative power have been constructed to predict the risk of non-sentinel lymph node (NSLN) metastasis in breast cancer prior to breast surgery after neoadjuvant chemotherapy (NAC). This study aimed to develop a new model for the prediction of NSLN metastasis in patients with initial clinical node positivity (cN+).Methods: The present study reviewed a total of 257 patients (179 in the training set and 78 in the testing set) with cN+ breast cancer who underwent both sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) following NAC. Univariate and multivariate analyses were used to select clinical factors affecting NSLN metastasis prior to breast surgery. A logistic regression model was developed based on these factors and the results of post-NAC axillary tail position on mammography (AT) and ultrasound (AUS).Results: Four factors with p<0.05 in the univariate analysis, including ycT0 (odds ratio [OR]: 4.84, 95% confidence interval [CI]: 2.13-11.91, p<0.001), clinical stage before NAC (OR: 2.68, 95% CI: 1.15-6.58, p=0.025), estrogen receptor (ER) expression (OR: 3.29, 95% CI: 1.39-8.39, p=0.009), and Her2 status (OR: 0.21, 95% CI: 0.08-0.50, p=0.001), were independent predictors of NSLN metastases. The clinical model based on the above data resulted in an AUC of 0.82 (95% confidence interval [CI]: 0.76-0.88) in the training set and 0.83 (95% CI: 0.74-0.92) in the validation set. The results of the post-NAC AUS and. AT were added to the clinical model to construct a clinical imaging model for the prediction of NSLN metastasis with an area under the curve of 0.87 (95% confidence interval [CI]: 0.81-0.93) in the training set and 0.89 (95% CI: 0.82-0.96) in the validation set.Conclusions: The present study incorporated the results of post-NAC AT and AUS with other clinal factors to develop a new model for the prediction of NSLN metastasis in patients with initial cN+ prior to breast surgery. This model performed excellently, allowing physicians to select patients for whom unnecessary ALND could be omitted after NAC.

Citation Format: Kun Wang, Teng Zhu, Tingfeng Zhang. A model incorporating axillary tail position on mammography for preoperative prediction of non-sentinel lymph node metastasis in patients with initial cN+ breast cancer after 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 P3-01-14.
Abstract P3-02-06: A phase II study of 68Ga-ABY-025 PET for non-invasive quantification of HER2 expression in breast cancer
Authors: Alhuseinalkhudhur Ali , Lindman Henrik , Liss Per , Sundin Tora , Frejd Fredrik Y , Hartman Johan , Iyer Victor , Lubberink Mark , Velikyan Irina , Sörensen Jens
Published: March 2022

Introduction/Aim: 68Ga-ABY-025 is a small-protein HER2-binder which has shown promising results in evaluating HER2 receptor status in earlier studies in breast cancer (BC). The aim of the current study was to investigate the role of 68Ga-ABY-025 PET imaging in relation to histopathology and treatment response. Methods: This single-center Phase II study consecutively included neoadjuvant patients with stage 2/3 BC (n=22) and recurrent metastatic BC (rMBC, n=18). All patients had at least one HER2-positive/borderline biopsy before inclusion and underwent 68Ga-ABY-025 PET at baseline followed by FDG PET/CT and biopsies for pathology analysis as part of study. FDG PET/CT was repeated after 2 cycles of treatment and glycolytic tumor burden (FDG2-FDG1)/FDG1) was calculated for up to five largest lesions in each patient. A reduction in glycolytic tumor burden >30% was considered good metabolic response. Uptake values (ABY-SUV) from 68Ga-ABY-025 PET in tumor lesions were compared with standard pathology analysis of tumor biopsies. Data was evaluated using regression and ROC analysis. Results: Biopsies for HER2 showed 32 positive, 3 borderline and 5 negative lesions. 68Ga-ABY-025 PET produced high-contrast images with ABY-SUV ranging from 0 to 50. Correlation of ABY-SUV and HER2 score from biopsies did not reach significance. HER2-targeted therapy in stage 2/3 BC resulted in a larger metabolic response (mean reduction of glycolytic tumor burden 70±26%) than in rMBC (mean reduction 25±61%, p<0.001). ABY-SUV correlated negatively with change in glycolytic tumor burden (p<0.0001) and ABY-SUV>6.0 predicted good metabolic response in soft-tissue tumors (AUC 0.82, 95% confidence interval 0.75-0.89, p<0.0001), corrected for neoadjuvant/recurrent setting. Using this cut-off, ABY SUV and invasive HER2 score were discordant in 12 of 40 patients (30%) - 6 with stage 2/3 BC and 6 with rMBC. Of the discordant cases, 68Ga-ABY-025 PET predicted the response correct in 7 cases (3 with stage 2/3 BC and 4 with rMBC) compared to biopsy-based pathology with correct prediction in 5 cases. Conclusion: 68Ga-ABY-025 PET is a potentially useful non-invasive indicator of in-vivo HER2 receptor status in breast cancer and might predict early response to HER2-targeted therapies. A larger multi-center study has been initiated to confirm these results.

Citation Format: Ali Alhuseinalkhudhur, Henrik Lindman, Per Liss, Tora Sundin, Fredrik Y Frejd, Johan Hartman, Victor Iyer, Mark Lubberink, Irina Velikyan, Jens Sörensen. A phase II study of 68Ga-ABY-025 PET for non-invasive quantification of HER2 expression 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 P3-02-06.
Abstract P3-06-03: NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells
Authors: Rodriguez-Tirado Carolina , Kale Nupura , Carlini Maria Jose , Shrivastava Nitisha , Rodrigues Alcina , Khalil Bassem , Bravo-Cordero Jose Javier , Alexander Melissa , Ji Jiayi , Sosa Maria Soledad
Published: March 2022

Pre-malignant cells disseminate during very early and sometimes asymptomatic stages of tumor progression. Once settled in permissive environments at secondary organs, they can act as a source for metastasis (e.g. in breast, pancreatic, colon, melanoma and lung carcinomas), thus emerging as important players in future prognosis. Granted that biological barriers to tumorigenesis exist, there must also be limiting steps to early dissemination in pre-malignant cells, all of which remain largely unknown. We report that the orphan nuclear receptor NR2F1/COUP-TF1, downstream of Her2 signaling via p38alpha serves as a barrier to early dissemination in pre-malignant breast cells. Our work shows that NR2F1 expression is positively regulated by p38α-MAPK pathway and inhibited by HER2 oncogenic signaling pathway. Furthermore, NR2F1 downregulation in human and murine pre-malignant cell lines led to a partial epithelial-to-mesenchymal transition characterized by decreased E-cadherin expression and β-catenin membrane localization, disorganized laminin 5 deposition, and increased expression of CK14, TWIST1, ZEB1 and PRRX1, thus explaining an increased motility and dissemination of early cells upon loss of NR2F1. Interestingly, NR2F1 lost also maintained epithelial markers (like CK18), suggesting an hybrid luminal-mesenchymal phenotype that could favor cellular plasticity to adapt to distant sites. We also showed that NR2F1 blocked b-catenin nuclear localization via a WNT-dependent pathway. Significantly, downregulation of NR2F1 increased the in vivo dissemination potential of pre-malignant cells to lungs in a HER2-dependent manner. Lastly, Nr2f1 expression was downregulated in non-invasive DCIS biopsies when compared to benign adjacent tissue, and its expression was inversely correlated to Prrx1 levels. The inverse correlation between Nr2f1 and Prrx1 levels was lost in genetically evolved primary tumors, which suggests that a unique inhibitory mechanism of dissemination dominates at early stages of tumor progression. Overall, our data suggest the existence of an inhibitory mechanism of dissemination regulated by NR2F1 downstream of HER2 signaling in premalignant breast cells and propose that therapeutic strategies that aim to maintain NR2F1 expression could reduce dissemination of premalignant cells and delay relapses.

Citation Format: Carolina Rodriguez-Tirado, Nupura Kale, Maria Jose Carlini, Nitisha Shrivastava, Alcina Rodrigues, Bassem Khalil, Jose Javier Bravo-Cordero, Melissa Alexander, Jiayi Ji, Maria Soledad Sosa. NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells [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 P3-06-03.
Abstract P3-10-02: Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic breast cancer
Authors: Lee Jieun , Joe Seung Yeon , Lee Ji-Sun , Kim Dong-Min , Lee Ahwon
Published: March 2022

Purpose Capecitabine is one of a treatment option in anthracycline and taxane pre-treated metastatic breast cancer (MBC) patients. We have performed miRNA microarray of durable and poor responders to capcitabine, and compared with cell line miRNA expression profile (MCF-7, tamoxifen-resistant MCF-7 [MCF-TAM] cell line treated with 5-FU. Methods Between Jan 2006 to Jan 2021, 66 patients treated with capecitabine after anthracycline and taxane failure were enrolled. Twenty-three archival tumor tissues (11 durables and 12 poor responders, each) were collected and went through nCounter miRNA expression assay. MCF-7, tamoxifen resistant MCF-7 (MCF-TAM) cell line was treated with tamoxifen or 5-FU for proliferation assay and also went through nCounter miRNA expression assay. Results HR positive patients who received anti-estrogen treatment before capecitabine showed longer PFS (median 7.7 vs. 4.03 months, P=0.006). MCF-7 treated with tamoxifen and 5-FU showed decreased proliferation compared to 5-FU treated MCF-7. There was significant difference of miR-579-3p expression between durable and poor responders (log2FC -3.02, P=0.004). Tamoxifen-treated MCF-7 cell line showed upregulation of miR-579-3p compared to MCF-7. Tamoxifen + 5-FU treated MCF-7 cell line showed decreased expression of miR-579-3p compared to 5-FU treated MCF-7 cell line. MCF-7 cell line was treated with 5-FU and miR-579-3p. Compared to 5-FU only treated cell line, 5-FU + miR-579-3p treated cell line showed trends for decreased cell proliferation, suggesting that miR-579-3p may have chemo-sensitizing role during systemic chemotherapy. Based on miRNA database, authors hypothesized that MDM2 may be target protein of miR-579-3p and planning to perform further analysis. Conclusions Anti-estrogen treatment before capecitabine administration was associated to better survival in HR positive MBC. Anti-estrogen potentiated the effect of 5-FU in MCF-7. MiR-579-3p was upregulated in durable responders and tamoxifen treated MCF-7 cell line. Further study is planned to analyze the role of miR-579-3p and its potential target, MDM2 in breast cancer.

Citation Format: Jieun Lee, Seung Yeon Joe, Ji-Sun Lee, Dong-Min Kim, Ahwon Lee. Enhanced miR-579-3p by anti-estrogen treatment may affect capecitabine response in hormone receptor positive metastatic 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 P3-10-02.
Abstract P3-12-18: Mortality after late breast cancer recurrence in Denmark
Authors: Pedersen Rikke Noergaard , Mellemkjær Lene , Ejlertsen Bent , Nørgaard Mette , Cronin-Fenton Deirdre
Published: March 2022

Purpose: Late recurrence (i.e., ≥10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of breast cancer (BC) death after late recurrence and identified prognostic factors. Furthermore, we compared survival between late and early recurrence. Methods: Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, ten years or 31/12/2018. We calculated mortality rates (MRs) per 1000 person-years (PY) and cumulative BC mortality, for early versus late recurrence and by characteristics of the primary tumor and of the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risk. Results: Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 3 years (MR= 84.8 per 1000 PY; 10-year cumulative mortality=50%). Among 1,573 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 2.6 years (MR= 173.9 per 1000 PY; 10-year cumulative mortality=72%). Advanced stage at primary diagnosis, distant metastases, and adjuvant recurrence treatments were associated with increased mortality, while breast-conserving surgery at primary diagnosis, loco-regional recurrence, and recurrence surgery were associated with lower mortality. Conclusion: Patients with late recurrence had a more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death.

Citation Format: Rikke Noergaard Pedersen, Lene Mellemkjær, Bent Ejlertsen, Mette Nørgaard, Deirdre Cronin-Fenton. Mortality after late breast cancer recurrence in Denmark [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 P3-12-18.
Abstract P3-13-07: A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer
Authors: Rennert Gad , Nehoray Bita , Lejbkowicz Flavio , Dishon Sara , Kalet Shiri , Herzog Joseph , Slavin Thomas , Castillo Danielle , Tsang Kevin , Sand Sharon , Rennert Hedy S , Weitzel Jeffrey
Published: March 2022

Background: After decades of research on Ashkenazi Jewish (AJ) founder mutations in BRCA1 and BRCA2 (BRCA), there is still little known about genetics in non-AJ and Arab breast cancer populations in Israel and non-BRCA pathogenic variants (PV) in the total population. We used multigene panel testing (MGPT) to characterize the spectrum and prevalence of PV in cancer susceptibility genes in various Jewish and Arab demographic subgroups. Methods: A population-based cohort of women diagnosed with breast cancer before the age of 46 in a defined geographical area in Northern Israel was recruited as part of the BCINIS study and underwent MGPT. Probability matrices of proportion of PV by gene, and by ethnic sub-group (AJs, Sephardi Jews of North African origin, Sephardi Jews of other Eastern origins, Arabs), age-sub-group (35 and under, 36-45) and first-degree family history of breast, ovary or pancreatic cancer were calculated. Results: Overall, 1650 women were tested, including 1012 Jewish, 530 Arab and 108 non-Jewish/non-Arab women. We detected 375 PV among 363 women (22.7%): 212 in AJ (33.4% of AJs), 61 in Sephardi Jews (14.2% of Sephardi), and 69 in Arabs (13.0% of Arab). Only 162 of the PV (43.2%) were the BRCA AJ founders, another 39 BRCA PV (10.4%) were reported previously, while 15 BRCA PV (4.0%) are likely private. The remaining non-BRCA PV (42.4%) were distributed across 18 genes, with findings predominantly in CHEK2, MUTYH, ATM, BLM, ERCC3, PALB2, and FANCA. The prevalence of PV varied significantly across the ancestral subsets, from 95.5% probability in AJ women diagnosed before age 36 and with first degree family history to only 9.3% in Arab women diagnosed at age 36-45 and without family history. Conclusions: In this comprehensive, population-based, cohort of women with young onset breast cancer, the presence of PV in more than 15 genes is compelling and informs a necessarily broader approach to genetic testing and counseling.

Citation Format: Gad Rennert, Bita Nehoray, Flavio Lejbkowicz, Sara Dishon, Shiri Kalet, Joseph Herzog, Thomas Slavin, Danielle Castillo, Kevin Tsang, Sharon Sand, Hedy S Rennert, Jeffrey Weitzel. A comprehensive germline genetic landscape in young Jewish & Arab women with 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 P3-13-07.