Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.

Anthracycline-based regimens have been an important treatment component for patients with breast cancer. As demonstrated in the last Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, anthracycline-based regimens decrease breast cancer mortality by 20-30%. Anthracycline toxicities include the rare-but potential morbid-cardiotoxicity or leukemogenic effect, and the almost universal-but very distressing-alopecia. Due to potential toxicities, and large number of patients being exposed, several worldwide trials have re-examined the role of anthracycline-based regimens in the management of breast cancer. Current literature supports that anthracyclines are not required for all patients with breast cancer and should be avoided in those with high cardiac risk. Recent results from the ABC trials suggest that anthracyclines should not be spared for patients with triple negative breast cancer (regardless of axillary node involvement) or HER2-/ER+ with significant node involvement. Based on current literature, for HER2-negative patients with low-risk breast cancer, anthracyclines could be spared with regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF) or docetaxel and cyclophosphamide (TC). Patients with intermediate or high-risk breast cancer should be considered for anthracycline-based regimens based on other factors such as age, comorbidities, tumor grade, lymphovascular invasion, and genomic profiling. Patients with HER2-positive breast cancer with low risk could be treated with paclitaxel and trastuzumab. For the remaining patients with HER2 overexpression, while docetaxel, carboplatin, and trastuzumab (TCH) has demonstrated to improve disease-free survival (DFS), anthracycline-containing regimens should be discussed, especially for those with very high-risk breast cancer. Although several biomarkers, such as topoisomerase II (TOP2A) and chromosome 17 centromeric duplication (Ch17CEP) have been proposed to predict benefit from anthracycline regimens, further research is required to delineate their proper utility in the clinical setting.

Metastatic dissemination in breast cancer is regulated by specialized intravasation sites called “tumor microenvironment of metastasis” (TMEM) doorways, composed of a tumor cell expressing the actin-regulatory protein Mena, a perivascular macrophage, and an endothelial cell, all in stable physical contact. High TMEM doorway number is associated with an increased risk of distant metastasis in human breast cancer and mouse models of breast carcinoma. Here, we developed a novel magnetic resonance imaging (MRI) methodology, called TMEM Activity-MRI, to detect TMEM-associated vascular openings that serve as the portal of entry for cancer cell intravasation and metastatic dissemination. We demonstrate that TMEM Activity-MRI correlates with primary tumor TMEM doorway counts in both breast cancer patients and mouse models, including MMTV-PyMT and patient-derived xenograft models. In addition, TMEM Activity-MRI is reduced in mouse models upon treatment with rebastinib, a specific and potent TMEM doorway inhibitor. TMEM Activity-MRI is an assay that specifically measures TMEM-associated vascular opening (TAVO) events in the tumor microenvironment, and as such, can be utilized in mechanistic studies investigating molecular pathways of cancer cell dissemination and metastasis. Finally, we demonstrate that TMEM Activity-MRI increases upon treatment with paclitaxel in mouse models, consistent with prior observations that chemotherapy enhances TMEM doorway assembly and activity in human breast cancer. Our findings suggest that TMEM Activity-MRI is a promising precision medicine tool for localized breast cancer that could be used as a non-invasive test to determine metastatic risk and serve as an intermediate pharmacodynamic biomarker to monitor therapeutic response to agents that block TMEM doorway-mediated dissemination.

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Introduction: Autoimmune hemolytic anemia (AIHA) is a rare condition that can cause potentially serious complications in pregnant women and newborns. With the lack of prospective trials, physicians often have to make treatment decisions for this vulnerable population based on scarce literature with poor evidence. We sought to summarize existing literature and analyze maternal and neonatal outcomes in pregnancy-associated AIHA (p-AIHA). Methods: Cases of AIHA in pregnancy were collected using MEDLINE/PubMed and Google Scholar literature search using terms "autoimmune hemolytic anemia" and "pregnancy". Bibliography of each article was hand-searched for additional reports. Only publications in English were included. Cases of preexisting AIHA, autoimmune disease associated AIHA, non-immune hemolysis, and cases where direct antiglobulin testing (DAT) was not performed, were excluded. Laboratory, obstetric, neonatal and treatment data were collected. Data were analyzed using descriptive statistics. We used Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. When missing data were encountered, we reported a valid number of analyzed patients in parentheses. Results: We identified 87 cases of p-AIHA from case reports, case series, abstracts and posters. Final analysis included 51 individual women. Median age at p-AIHA presentation was 28 years. Presentation was less common in the first pregnancy (34%); most cases presented in the second or third trimester (83.3%).Median nadir hemoglobin (Hb), lactate dehydrogenase, total bilirubin and peak reticulocyte count were 5.8 g/dL, 457 U/L, 2.2, and 13.6%, respectively. DAT negative hemolysis was reported in 41% of cases (Table 1). DAT positivity was not associated with pregnancy trimester, hemolysis severity, response to steroids, AIHA recurrence, adverse pregnancy outcomes, or hemolysis in newborn. There was a trend for longer duration of hemolysis postpartum in women with positive DAT compared to negative DAT (10 vs 2 weeks, p = 0.08). Median duration of hemolysis postpartum was 6 weeks (n=27, range 0-96 weeks). Two thirds of women were treated with steroids with hemoglobin response of 88.9% (n=27). There was no association between steroid use and duration of hemolysis postpartum. Blood transfusion was administered in 27 out of 33 women, with a median number of units transfused 5. Recurrent p-AIHA was seen in 40% (12/30) of women; there was no difference in nadir Hb levels for those with recurrent p-AIHA vs. not recurrent (6.8 vs 5.2 g/dL, p=0.11). Pregnancy resulted in term delivery in 61.9%, preterm delivery in 23.8%, and stillbirth in 9.5% (n=42). Adverse pregnancy outcomes, which included preterm labor and stillbirth, were reported in 50% of women who presented in the first or second trimester compared to 16% who presented in the third trimester (p=0.049, Table 2).Women with adverse pregnancy outcomes had significantly lower median nadir hemoglobin compared to women without adverse pregnancy outcomes (4.3 and 6.2 p = 0.0078) and were more likely to receive transfusion (73% and 56%, p= 0.071). Hemolysis at birth was reported in 59% (n=22) of newborns with available data with 13 neonates (38%) requiring transfusion support . Use of steroids had no effect on presence of hemolysis in the newborn. Conclusions: We present the largest cohort of p-AIHA described in the literature. Our study reports that p-AIHA is uncommon in primigravidas and typically presents later in pregnancy. Presentation in first or second trimester in pregnancy and lower Hb nadir were significantly associated with adverse pregnancy outcomes. Steroids and blood transfusions were needed in most patients, and hemolysis persisted on average for 6 weeks postpartum. There was a high frequency of Coombs negativity which was associated with shorter duration of postpartum hemolysis. Preterm labor and stillbirth were observed in 33.3% of pregnancies. The incidence of hemolysis in newborns from p-AIHA mothers is very high and is often clinically significant. Recurrence in subsequent pregnancy is common but has similar Hb nadir as non-recurrent cases. This study provides insights into the clinical course of pregnancy and neonatal outcomes in p-AIHA. Our findings may help guide management of this rare condition. A prospective study of patients with p-AIHA is needed to determine optimal therapy to reduce antepartum and neonatal complications. Figure 1 Figure 1. Disclosures Murakhovskaya: Alexion, Rigel, Bioverativ/Sanofi, Momenta, Annexion, Incyte: Research Funding; Bioverativ/Sanofi, Momenta, Apellis, Novartis: Consultancy; Cardiff Oncology, Trillium Therapeutics: Current holder of individual stocks in a privately-held company.

PURPOSE The HOLA COVID-19 study sought to evaluate the impact of COVID-19 on oncology practices across Latin America (LATAM), challenges faced by physicians, and how practices and physicians adapted while delivering care to patients with cancer. METHODS This international cross-sectional study of oncology physicians in LATAM included a 43-item anonymous online survey to evaluate changes and adaptations to clinical practice. Multivariable logistic regression analyses were used to evaluate the association of caring for patients with COVID-19 and changes to clinical practice. RESULTS A total of 704 oncology physicians from 19 countries completed the survey. Among respondents, the most common specialty was general oncology (34%) and 56% of physicians had cared for patients with COVID-19. The majority of physicians (70%) noted a decrease in the number of new patients evaluated during the COVID-19 pandemic when compared with prepandemic, and 73% reported adopting the use of telemedicine in their practice. More than half (58%) of physicians reported making changes to the treatments that they offered to patients with cancer. In adjusted models, physicians who had cared for patients with COVID-19 had higher odds of changing the type of chemotherapy or treatments that they offered (adjusted odds ratio 1.81; 95% CI, 1.30 to 2.53) and of delaying chemotherapy start (adjusted odds ratio 2.05; 95% CI, 1.49 to 2.81). Physicians identified significant delays in access to radiation and surgical services, diagnostic tests, and supportive care. CONCLUSION The COVID-19 pandemic has significantly disrupted global cancer care. Although changes to health care delivery are a necessary response to this global crisis, our study highlights the significant disruption and changes to the treatment plans of patients with cancer in LATAM resulting from the COVID-19 health care crisis.

Purpose: CDK4/6i combined with endocrine therapy have improved HR+/HER2-metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends strati ed by race in patients with HR+/HER2-MBC after the approval of CDK4/6i, as part of the standard of care, in 2015.Methods: We performed a population-based study using the SEER database. Patients with HR+/HER2-MBC were divided into two time-based cohorts: 1) 2011-2013, corresponding to the pre-CDK4/6i era, and 2) 2015-2017 to the post-CDK4/6i era. We used propensity score matching and identi ed 2,684 patients in each cohort that matched in several characteristics. Kaplan-Meier curves and Cox proportional hazard models were used to estimate 2-year OS.Additionally, we compared survival between groups with a strati ed log-rank test. Lastly, we compared OS and breast cancer death risk between cohorts (strati ed by race) using Fine and Gray model. Results:The 2-year OS rate was 65% for the post-CDK4/6i group and 62% for the pre-CDK4/6i cohort (strati ed logrank p=0.025). The 2-year OS for NHW patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p=0.033). However, OS did not improve for NHB (54% vs. 54%, p=0.876) or Hispanic (67% vs 65%, p=0.617) groups.Conclusions: Our study con rms that outcomes for HR+/HER2-MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without signi cant improvement in OS in NHB or Hispanics.

Purpose: CDK4/6i combined with endocrine therapy have improved HR+/HER2- metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR+/HER2- MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. Methods: We performed a population-based study using the SEER database. Patients with HR+/HER2- MBC were divided into two time-based cohorts: 1) 2011-2013, corresponding to the pre-CDK4/6i era, and 2) 2015-2017 to the post-CDK4/6i era. We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan-Meier curves and Cox proportional hazard models were used to estimate 2-year OS. Additionally, we compared survival between groups with a stratified log-rank test. Lastly, we compared OS and breast cancer death risk between cohorts (stratified by race) using Fine and Gray model. Results: The 2-year OS rate was 65% for the post-CDK4/6i group and 62% for the pre-CDK4/6i cohort (stratified log-rank p=0.025). The 2-year OS for NHW patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p=0.033). However, OS did not improve for NHB (54% vs. 54%, p=0.876) or Hispanic (67% vs 65%, p=0.617) groups. Conclusions: Our study confirms that outcomes for HR+/HER2- MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics.