Therapy For Metastatic Breast Cancer Research Articles

Role of Ganetespib, an HSP90 Inhibitor, in Cancer Therapy: From Molecular Mechanisms to Clinical Practice.

Heat-shock proteins are upregulated in cancer and protect several client proteins from degradation. Therefore, they contribute to tumorigenesis and cancer metastasis by reducing apoptosis and enhancing cell survival and proliferation. These client proteins include the estrogen receptor (ER), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), human epidermal growth factor receptor 2 (HER-2), and cytokine receptors. The diminution of the degradation of these client proteins activates different signaling pathways, such as the PI3K/Akt/NF-κB, Raf/MEK/ERK, and JAK/STAT3 pathways. These pathways contribute to hallmarks of cancer, such as self-sufficiency in growth signaling, an insensitivity to anti-growth signals, the evasion of apoptosis, persistent angiogenesis, tissue invasion and metastasis, and an unbounded capacity for replication. However, the inhibition of HSP90 activity by ganetespib is believed to be a promising strategy in the treatment of cancer because of its low adverse effects compared to other HSP90 inhibitors. Ganetespib is a potential cancer therapy that has shown promise in preclinical tests against various cancers, including lung cancer, prostate cancer, and leukemia. It has also shown strong activity toward breast cancer, non-small cell lung cancer, gastric cancer, and acute myeloid leukemia. Ganetespib has been found to cause apoptosis and growth arrest in these cancer cells, and it is being tested in phase II clinical trials as a first-line therapy for metastatic breast cancer. In this review, we will highlight the mechanism of action of ganetespib and its role in treating cancer based on recent studies.

Targeted Two-Step Delivery of Oncotheranostic Nano-PLGA for HER2-Positive Tumor Imaging and Therapy In Vivo: Improved Effectiveness Compared to One-Step Strategy

Therapy for aggressive metastatic breast cancer remains a great challenge for modern biomedicine. Biocompatible polymer nanoparticles have been successfully used in clinic and are seen as a potential solution. Specifically, researchers are exploring the development of chemotherapeutic nanoagents targeting the membrane-associated receptors of cancer cells, such as HER2. However, there are no targeting nanomedications that have been approved for human cancer therapy. Novel strategies are being developed to alter the architecture of agents and optimize their systemic administration. Here, we describe a combination of these approaches, namely, the design of a targeted polymer nanocarrier and a method for its systemic delivery to the tumor site. Namely, PLGA nanocapsules loaded with a diagnostic dye, Nile Blue, and a chemotherapeutic compound, doxorubicin, are used for two-step targeted delivery using the concept of tumor pre-targeting through the barnase/barstar protein "bacterial superglue". The first pre-targeting component consists of an anti-HER2 scaffold protein, DARPin9_29 fused with barstar, Bs-DARPin9_29, and the second component comprises chemotherapeutic PLGA nanocapsules conjugated to barnase, PLGA-Bn. The efficacy of this system was evaluated in vivo. To this aim, we developed an immunocompetent BALB/c mouse tumor model with a stable expression of human HER2 oncomarkers to test the potential of two-step delivery of oncotheranostic nano-PLGA. In vitro and ex vivo studies confirmed HER2 receptor stable expression in the tumor, making it a feasible tool for HER2-targeted drug evaluation. We demonstrated that two-step delivery was more effective than one-step delivery for both imaging and tumor therapy: two-step delivery had higher imaging capabilities than one-step and a tumor growth inhibition of 94.9% in comparison to 68.4% for the one-step strategy. The barnase*barstar protein pair has been proven to possess excellent biocompatibility, as evidenced by the successful completion of biosafety tests assessing immunogenicity and hemotoxicity. This renders the protein pair a highly versatile tool for pre-targeting tumors with various molecular profiles, thereby enabling the development of personalized medicine.

Abstract P6-05-36: Cost-effectiveness of CDK4/6 inhibitors as a First line Therapy for Metastatic Breast Cancer. A Mexican Cohort

Abstract BACKGROUND. Breast cancer is the most frequent neoplasm worldwide, as reported by GLOBOCAN 2020, there were 2.2 million new cases per year and 680,000 deaths. In Mexico, it represents the leading cause of death from cancer in women, and therefore represents a public health problem in our country. The standard treatment for patients with hormone receptor-positive, her2-negative breast cancer is endocrine tehrapy with an aromatase inhibitor plus a CDK4/6 inhibitor (CDK4/6i+AI), however access to these therapies is difficult and limited resources in developing countries, lead to treatment strategies such as aromatase inhibitors alone (AI) or chemotherapy (ChT) still being used. However, management with ChT involves an increase in the use of reosurces due to cost per infusión, use of premedication and granulocyte colony-stimulating agents. OBJECTIVE The aim of this study was to provide an economic evaluation of CDK4/6i+AI compared with AI alone or ChT as a first line in MBC to better understand its value from the healthcare point of view in a developing country. METHODS. We designed a retrospective cost-effectiveness analysis of three different therapies CDK4/6i+AI, AI alone and ChT administered as first-line therapy for patients with MBC. RESULTS. A cost-effectiveness analysis was performed on a retrospective cohort of 150 MBC patients (march 2011 to April 2020) with a follow-up of al least 2 years. The median age at diagnosis was 55 years old. The utilization of health care resources was retrieved from clinical charts. Only direct costs associated with pre-progression, progression, and management of adverse events were considered and expressed on current USD. Seventy-six percent were diagnosed with de novo stage IV disease, 66% were postmenopausal and 76% had ductal histology. The most common sites of metastasis were visceral 55% and 29% had only bone metastases. We identified 3 treatment groups: (1) CDK4/6i+AI, 18.66% (28/150), (2) AI, 48.66% (73/150) and (3) ChT, 32.66% (49/150). The median PFS of iCDK4/6 + TH was 32.10 months compared with 18.87 (95%CI: 16.4, 28.7) months for the AI group and 6.57 months for chemotherapy. The HR of iCDK4/6+TH vs HT was 0.357 (95%CI: 0.18-0.72) and that of iCDK4/6+TH vs chemotherapy was 0.09 (95%CI: 0.04-0.22). Median OS survival was not reached in any arm. The most frequent adverse events grade 3 were fatigue 10.71%, neutropenia 32.14%, diarrhea 7.14%, myalgias 3.57% and arthralgias 3.57% in the CDK4/6i +AI group, fatigue 2.74% and arthralgias 4.11% in AI group and fatigue 20.41%, neutropenia 18.37%, nausea 10.2%, diarrhea 6.12%, myalgias 2.4% and headache 2.4% with chemotherapy. PFS was used as the outcome for the cost-effectiveness analysis, with 5 years of follow-up, CDK4/6i+AI offer an incremental efficacy of 1.4 years in PFS compared with AI and 2.43 years with ChT, they are related to an incremental cost of $28,151.61 and $26,720.47 concerning AI and ChT, respectively. The ICER for CDK4/6i+AI compared to AI is $20,108.29 and $10,996.07 compared to chemotherapy. CONCLUSION. CDK4/6i+AI increase years of life gained when compared to AI and chemotherapy. Is a cost-effective tratment in our institution because it is less than two GDP per capita. CDK4/6i+AI is the standar treatment around the world even in develop countries like Mexico. PFS 3 arms PFS 3 arms Citation Format: Maritza Ramos-Ramírez, Silvia Guzman-vazquez, Vanessa Dominguez-Esquivel, Jose Rodrigo Espinosa-Fernandez, Sandy Ruiz-Cruz, Paula Cabrera-Galeana, Alexandra Garcilazo, Luis Antonio Cabrera-Miranda, Claudia Haydee Arce Salinas. Cost-effectiveness of CDK4/6 inhibitors as a First line Therapy for Metastatic Breast Cancer. A Mexican Cohort. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-36.

Abstract P1-03-03: Real-World Treatment Patterns and Clinical Outcomes in Patients Treated with Eribulin After Prior PI3K Inhibitor Therapy for Metastatic Breast Cancer

Abstract Background: Eribulin has been used in the treatment of metastatic breast cancer (MBC) following approval in 2010 in the United States (US). Recently, several new therapeutic classes have been approved for patients with MBC, including the phosphoinositide 3-kinase (PI3K) inhibitor alpelisib. This study aimed to assess the treatment patterns and clinical outcomes in patients with MBC treated with eribulin following alpelisib in US clinical practice. Methods: A retrospective, noninterventional medical chart review study was performed to obtain de-identified patient data via participating oncologists. Study population included adult female patients with a diagnosis of MBC who initiated eribulin therapy between March 1, 2019, and September 30, 2020, following prior therapy with alpelisib. Eribulin treatment parameters and patient characteristics were captured. Progression-free survival (PFS) and overall survival (OS) since eribulin initiation was assessed using Kaplan-Meier methods. Results: This interim analysis included 47 eligible patients (median age 62 years at eribulin initiation; 77% Caucasian). The majority (91.5%) of this cohort had HR+/HER2– MBC; 72.3% had a known PIK3CA mutation. Eribulin was classified as 2nd line, 3rd line, and 4th line or later in 34%, 47%, and 19% of patients, respectively, in regard to the line of therapy in the metastatic setting. At last follow-up, eribulin treatment was ongoing for 34% of patients. The median treatment duration was 5.2 months (q1, q3: 3.9, 7.1) among those who had discontinued eribulin, and 11.3 months (q1, q3: 10.0, 13.7) among those who were still on treatment. At last follow-up, 72.3% of patients were alive. The estimated PFS rate at 12 months was 57.1% (95% CI: 40.0-70.9). Median was not reached for OS after initiation of eribulin; the estimated OS rates at 12 and 24 months were 80.2% (95% CI: 65.3-89.2) and 61.8% (95% CI: 37.2-79.2), respectively. Conclusion: Among patients with MBC who initiated eribulin following prior treatment with a PI3K inhibitor, over 60% were estimated to survive for at least 2 years. Future studies to confirm these results are warranted. Citation Format: Ravi K. Goyal, Jingchuan Zhang, Keith L. Davis, Peter A. Kaufman. Real-World Treatment Patterns and Clinical Outcomes in Patients Treated with Eribulin After Prior PI3K Inhibitor Therapy for Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-03-03.

Abstract P4-01-38: A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted a non-randomized, open-label, single-arm, multicenter, phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women. Primary objective was progression free survival, PFS. Secondary objectives: objective response rate, ORR (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate, CBR (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 6/30/2022 data cut-off, 2 pts were still on treatment. This is an updated analysis with median follow-up time of 24 months (range 8-51). Median age was 60 (range 39-82). The median PFS was 19.8 months with 95% CI (8-41) for pts with de-novo MBC and 7 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 77% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for AA pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients (8%) developed thromboembolic events (grades 2, 3, 4) and discontinued treatment. One patient died while on treatment from PD. More than 800 exosome proteins were detected in the samples analyzed so far. Exosomal protein networks in pretreatment samples predicted treatment response with 89% sensitivity and 95% specificity in unsupervised clustering. Data on correlative objectives will be presented in a separate abstract. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who present with de-novo metastatic disease and are intolerant to AI; although this small study indicates a lower PFS. Table 1: Baseline Demographics Citation Format: Oana C. Danciu, Kent Hoskins, Jennifer Weiss, Cristina I. Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Yu Gao, Menggang Yu, Qianqian Zhao, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski. A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-38.

Abstract P4-03-30: Patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer

Abstract Background: Tucatinib is an oral HER2-targeted therapy that was approved by the FDA in April 2020 for use in combination with trastuzumab and capecitabine for treatment of patients with previously treated HER2+ metastatic breast cancer (MBC). In the randomized HER2CLIMB trial median (95% CI) overall survival (mOS) and progression-free survival (PFS) for patients receiving tucatinib with trastuzumab and capecitabine were 21.9 (18.3, 31.0) and 7.8 (7.5, 9.6) months, respectively. HER2CLIMB utilized a placebo + trastuzumab + capecitabine comparator arm and included patients with active and stable brain metastasis (BM). Objectives: Describe patient characteristics, treatment patterns, and clinical outcomes for tucatinib-based treatment in the real-world setting. Methods: This retrospective cohort study included patients treated for HER2+ MBC between January 2017 and March 2022 in the nationwide de-identified electronic health record-derived Flatiron Health Metastatic Breast Cancer database who received tucatinib-based treatment outside of a clinical trial setting. Demographic and clinical characteristics of patients were described at baseline (MBC diagnosis) as well as at initiation of each oncologist-defined, rule-based line of therapy (LOT). Key outcomes included time to next treatment (TTNT), persistence, and mOS. Results: Of 2,057 patients treated for HER2+ MBC in the study period who met the inclusion criteria, 154 received tucatinib-based treatment. Of these patients, 18 (12%), 44 (29%), 33 (21%) and 59 (38%) received tucatinib-based treatment in the first-line (1L), second-line (2L), third-line (3L), and fourth-line or further (4L+) respectively. Median age at MBC diagnosis was 54 years. Median follow-up from tucatinib-based treatment initiation was 8.6 months. Overall, 106 (69%) had BM prior to initiating tucatinib therapy (14 [78%], 37 [84%], 20 [61%], and 35 [59%] in 1L, 2L, 3L, and 4L+ respectively). Those with BM initiated tucatinib-based treatment after a median of 2 prior therapies, compared with 2.5 in the non-BM group. The most common metastatic treatment regimens prior to 2L tucatinib-based treatment were trastuzumab + pertuzumab-based, and the most common regimens immediately following 2L tucatinib-based treatment were trastuzumab-based and trastuzumab deruxtecan. The most common regimens immediately prior to and following 3L tucatinib-based treatment were T-DM1 and trastuzumab deruxtecan, respectively. The median (95% CI) TTNT was 8.4 (6.3, 11.3) months overall, and 12.8 (5.5, not reached [NR]) months, 9.8 (4.8, NR) months, and 9.5 (6.1, 15.3) months in 1L, 2L, and 3L, respectively, the median OS was not reached overall (Table 1). Of patients with sufficient follow-up since treatment initiation, 65% (62/96) remained on tucatinib-based treatment after 6 months and 40% (20/50) after 12 months. Conclusion: The majority of patients receiving tucatinib-based treatment in clinical practice have BM at treatment initiation, constituting a larger proportion of the population than in HER2CLIMB (47.5% of patients). Tucatinib-based treatment use in the real-world setting is associated with a similar mOS and TTNT as in HER2CLIMB. Table 1: Median overall survival and time to next treatment in HER2CLIMB and this study *Time to next treatment was used as a proxy for progression-free survival in the HER2CLIMB clinical trial population. CI, confidence interval; mOS, median overall survival; NR, not reached; TTNT, time to next treatment. Citation Format: Peter A. Kaufman, Edward Neuberger, Ling-I Hsu, Naomi Schwartz, Karen Bartley, Shu Wang, Yutong Liu, Matthew T. Blahna, Brian T. Pittner, Gabriel Wong, Carey Anders. Patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-30.

Abstract P4-01-39: Real-world efficaccy of dual antiHER2 therapy in first line metastatic HER2-positive breast cancer and the possibility of prediction of long-term response

Abstract Background: Although huge progress has been made in treating HER2-positive metastatic breast cancer in the last decade, it remains an incurable disease. Dual anti-HER2 therapy with pertuzumab and trastuzumab combined with chemotherapy represents the standard first line treatment of metastatic HER2-positive breast cancer, in view of the impressive CLEOPATRA study results. The aim of this study was to analyze the efficacy of dual antiHER2 therapy in real-world clinical practice and determine the differences in the clinicopathological characteristics of the long-term responders in comparison with short-term responders. Methods: Retrospective analysis of dual antiHER2 therapy efficacy was done and correlated to clinical and pathological characteristics of patients with different duration of response (DoR) in the first line metastatic HER2-positive breast cancer. The study was conducted at the UHC Zagreb, Croatia and approved by the Ethics Committee. Long-term responders were defined as patients with a duration of response (DoR) to dual antiHER2 therapy ≥ 36 months, and short-term responders were defined as patients with DoR ≤ 12 months. Progression-free survival was estimated using the Kaplan-Meier method. The reverse Kaplan-Meier method was used to estimate median follow-up duration. The non-parametric Chi-Square test (between categorical variables) and Mann-Whitney U-test (between continuous variables) were used to determine the differences between long-term and short-term responders groups. The significance level was set at p < 0.05. Results: Altogether, 128 patients treated with dual antiHER2 therapy for HER2-positive metastatic breast cancer from October 2015 to May 2022 were included in the study. By data cut-off, 50.8 % (N=63) of patients had progressed or died. The median follow-up time was 36 months. The median PFS was 31 months for the total cohort (95% CI 22.6 -39.3). Overall, 29 patients among the long-term responders and 32 patients in the short-term responders group were identified. A comparison of clinical and pathological characteristics between the two groups is shown in Table 1. Even though patients in the group of long-term responders were younger (54.5 years vs. 56.5 years), had less visceral involvement (69 % vs. 81.3%), and were more often trastuzumab ”naive“ (75.9% vs. 68.7%), no statistically significant differences were found between the two groups. Conclusion: In this real-life study, the median PFS was 31 months for the total cohort, even longer than in the referent CLEOPATRA trial, which confirms the effectiveness of dual antiHER2 therapy in a real-world setting. No possible clinical or pathological predictors of long-term response were identified, but larger studies may be able to distinguish patients’ characteristics associated with long-term response. Table 1: A comparison of clinical and pathological characteristics between the group of long-term responders and short-term responders Citation Format: Marija Križić, Tajana Silovski, Marina Popović, Natalija Dedić Plavetić. Real-world efficaccy of dual antiHER2 therapy in first line metastatic HER2-positive breast cancer and the possibility of prediction of long-term response [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-39.

Abstract P1-08-07: Educational Opportunities to Improve HER2 Testing and Use of Newer Therapies for HER2-Positive MBC Among Community Healthcare Professionals

Abstract Background: The management of HER2-positive (HER2+) metastatic breast cancer (MBC) has continued to evolve, with multiple FDA approvals of novel HER2-targeted agents since late 2019. Considering the growing HER2+ MBC treatment armamentarium and the emerging HER2-low MBC subtype, we undertook an analysis of the current implementation of guideline and expert recommendations for HER2 testing and treatment of HER2+ MBC with recently approved agents among oncology healthcare professionals (HCPs) participating in educational programs on these topics. Methods: Between January 2020 and April 2022, we conducted several expert-designed educational activities for HCPs focusing on recommended HER2 testing and treatment of HER2+ MBC. Polling questions on HCP knowledge, practice patterns, and confidence in the evaluation of HER2 status and the use of newer targeted therapies in the setting of HER2+ MBC were assessed across the activities and compared with expert recommendations. Results: Among 129 HCPs participating in 2 educational activities held from July 2020 to March 2021, 53% reported confidence to appropriately apply current HER2 testing guidelines to patient care. Similarly, among 407 HCPs who participated in 4 educational programs from May 2020 to January 2021, 24% reported confidence to incorporate recently approved drugs (including trastuzumab deruxtecan [T-DXd], neratinib, and tucatinib) into the care of patients with HER2+ MBC. The percentage of HCPs reporting confidence in the use of these new drugs remained low over this time period. Comparison of treatment recommendations for various HER2+ MBC case scenarios across 7 educational activities from January 2020 through April 2022 showed considerable discordance between experts and HCPs regarding the implementation of newly approved HER2-targeted regimens (Table 1). For patients with disease progression after 2 lines of therapy and no central nervous system (CNS) metastases, 27% to 57% of HCPs (n = 571) chose T-DXd in agreement with experts. For patients with disease progression after 2 lines of therapy with CNS metastases, 27% to 42% of HCPs (n = 597) chose a tucatinib-based regimen in agreement with experts. Treatment choice concurrence between HCPs and experts did not increase over the course of this study for either of these patient scenarios. Conclusions: These data suggest that some HCPs are challenged to optimally incorporate recommendations for HER2 testing and the implementation of novel HER2-targeted therapies in the care of patients with HER2+ MBC. Educational activities designed to improve the knowledge and confidence of HCPs would benefit patients with HER2+ MBC. A detailed analysis of trends over time and by role on the care team will be presented. Table 1. Expert and HCP Treatment Selections for Case Scenarios in HER2+ MBC. Citation Format: Ryan P. Topping, Rachael M. Andrie, Kristen Rosenthal, Timothy A. Quill. Educational Opportunities to Improve HER2 Testing and Use of Newer Therapies for HER2-Positive MBC Among Community Healthcare Professionals [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-08-07.

Abstract OT3-16-01: On-going prospective study to measure serum progranulin/GP88 levels in metastatic breast cancer patients in association with disease status

Abstract The ability to monitor response to therapy and disease progression in metastatic breast cancer (MBC) patients is a major step in patient management. Imaging is the method of choice for the assessment of disease status and the monitoring of disease progression. However, this approach remains expensive, expose patients to radiation and thus is mainly performed every 2-3 months. During this time interval, the disease may progress significantly on ineffective treatment and the patient may present treatment related toxicities due to the inability to detect progression at earlier times. Circulating levels of tumor associated biomarkers such as CA15-3 and CEA are often determined to track disease status of MBC. However, even though they can provide information about disease progression, they do not always provide a reliable measure of response to therapy. The monitoring of disease status and progression through the measurement of drivers of disease should provide an alternative and complementary approach to existing strategies in order to better to monitor the disease status and enable proactive management of MBC patients. Progranulin also called Glycoprotein 88kDa (PGRN/GP88) is an autocrine growth factor overexpressed in breast cancer. Biological studies have established GP88 as a critical player in breast tumorigenesis. GP88 overexpression is associated with the malignant phenotype, estrogen independence, increased proliferation, survival, and drug resistance. High PGRN/GP88 tumor expression measured by immunohistochemistry in invasive ductal carcinoma is an independent prognostic marker associated with increased risk of recurrence and mortality. Clinical studies have demonstrated that GP88 circulating levels as measured by enzyme immunoassay are elevated in breast cancer patients, compared to healthy individuals. In MBC patients, circulating GP88 levels correlate with overall survival. These facts are supportive of the hypothesis that the measurement of circulating GP88 levels in MBC patients can serve as an additional biomarker to monitor MBC disease status and be predictive to outcome. A prospective study was established is to identify whether there is a statistically significant change in serum GP88 levels associated with time to progression of breast cancer as measured by RECIST 1.1 criteria in MBC patients. With the assumptions that patients will provide a baseline and four follow up visits and that 20% of the visits record a disease progression, time to progression. Taking the plausible and clinically relevant performance to be 75% sensitivity and 46% false positive, a sample of ninety patients would give 85% power. Under IRB approved protocols at the University of Maryland Greenebaum Comprehensive Cancer Center and at two Baltimore Medstar Health Facilities, a total of 103 female breast cancer patients with measurable or evaluable metastatic disease will be consented and enrolled. The patients have been re-staged within 4 weeks and will continue or begin new therapy. Currently, we have enrolled sixty-five subjects at the three facilities. In addition to standard laboratory assessment and radiographic imaging/staging every 2-3 months on study, blood samples will be collected from each patient. The samples are stored at -70C until evaluated for GP88 using a GP88 enzyme linked immunoassay. We will analyze the GP88 serum level in correlation with survival and with disease status determined as responder, stable or progressing based on the RECIST criteria. This study is supported by grant R44CA210817 from the National Cancer Institute to Ginette Serrero Principal Investigator. Citation Format: Ginette Serrero, Paula Rosenblatt, Nancy Tait, Barbara Rector, Jennifer A. Latteri, Binbin Yue, Katherine Tkaczuk. On-going prospective study to measure serum progranulin/GP88 levels in metastatic breast cancer patients in association with disease status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-16-01.

Abstract P1-11-16: Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study

Abstract Background Trastuzumab emtansine (T-DM1) has shown great effectiveness in treating HER2-positive metastatic breast cancer, but therapies subsequent to T-DM1 failure remain controversial. Here, we investigated efficacy and safety of tyrosine kinase inhibitors (TKIs) based therapy in T-DM1 resistant HER2-positive metastatic breast cancer. Methods From August 2019 to April 2022, 53 HER2-positive metastatic breast cancer patients received TKIs-based therapy after T-DM1 failure in Jiangsu Province Hospital. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles were reported. Results 53 patients received TKIs-based therapies as a second or later line therapy. 51 (96.2%) patients received a combined therapy, including TKIs plus capecitabine, vinorelbine or trastuzumab. 2 (3.7%) patients received TKIs alone. The median follow-up time was 19.7 months (95%CI 15.4-24.0). The median PFS was 11.9 months (95%CI 7.9-15.9). OS has not reached. ORR was 19.6% and CBR was 72.5%. For patients who had brain metastasis (n=12), the median PFS was 10.5 months (95%CI 7.5-13.5) and intracranial ORR was 33.3%. Compared with lapatinib (n=30), pyrotinib (n=21) provided a better PFS after T-DM1 progression (8.0 months vs. 19.0 months, P=0.033). The most common adverse events were thrombocytopenia (12, 23.6%), diarrhea (8, 15.7%), leucopenia (8, 15.7%) and hand-foot syndrome (8, 15.7%). Conclusion TKIs-based therapy could prolong the survival of HER2-positive metastatic breast cancer patients after T-DM1 failure, including those with brain metastases. Compared with lapatinib, pyrotinib might provide better outcomes for overcoming T-DM1 resistance. Citation Format: Yongmei Yin, Wei Li, Xiang huang, Chunxiao Sun, Yijia Hua, Nan Jin, Xinyu Wu. Treatment with tyrosine kinase inhibitors (TKIs) in HER2-positive metastatic breast cancer after trastuzumab emtansine (T-DM1) failure: A real-world study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-16.

Abstract P2-23-10: Gene expression and mutation profiles in HER2-mutated metastatic breast cancer

Abstract Background: HER2 activating mutations occur in 2-5% of metastatic breast cancer (MBC) patients. These mutations cluster in the kinase domains and at amino acids 309-310 in the extracellular domain. The MutHER, SUMMIT, and PlasmaMATCH clinical trials have shown neratinib monotherapy or neratinib plus fulvestrant combination produce clinical benefit in 28% to 46% in HER2-mutated MBC patients, but median progression-free survival was only 3.6 to 5.4 months. In order to improve the knowledge and outcomes for patients with HER2-mutated MBC, we compared the mutational landscape and gene expression of HER2-mutated MBC patients to HER2-amplified and HER2-wild type MBC patients. Methods: De-identified data from a cohort of stage 4 breast cancer patients (n=1,834) sequenced with the Tempus xT (DNA-seq of 595-648 genes, whole exome-capture RNA-seq) solid tumor assay was retrospectively analyzed. The most recent sample of the patient was used for analyses. Patients were stratified by HER2 mutational status: HER2-wild type (HER2-wt), HER2-amplifications (HER2-amps), or HER2-mutants (HER2-muts). Additionally, a sub-analysis was conducted among HER2-mutants to compare kinase domain mutations to other HER2 mutations. Patient demographic characteristics were compared between groups along with the prevalence of individual gene alterations (pathogenic/likely pathogenic short variants and copy number alterations), adjusted for false-discovery. Results: Within the cohort, 62 (3.4%) patients harbored HER2-muts tumors and 125 (6.8%) patients had HER2-amps tumors. Three patients, whose tumors had both HER2 mutation and amplification, were classified among the HER2-muts. Relative to the HER2-wt cohort (median = 53 yo), HER2-muts patients were older (median = 55 yo) while HER2-amps patients were younger (median = 49 yo) (P< 0.001). Significant differences were observed in genomic alterations co-occurring with HER2-muts compared to HER2-wt and HER2-amps, including CDK12 (4.8% vs 0.2% vs 74%), CDH1 (44% vs 11% vs 4.8%), ESR1 (4.8% vs 21% vs 8.8%), TOP2A (3.2% vs 0.5% vs 14%), and ERBB3 (11% vs 0.9% vs 0.8%). Of note, the majority of CDK12 mutations are amplifications (96%). Median HER2 mRNA log10 gene expression differed among the three cohorts (HER2-muts (3.79), HER2-wt (3.56), HER2-amps (4.54); P< 0.001). Among HER2-muts patients, 46 (74.2%) patients had HER2 kinase domain mutations (HER2-kinase). Relative to other HER2-muts patients, HER2-kinase patients displayed a lower prevalence of CDH1 mutations (35% vs 69%; P = 0.018). No significant differences were noted in ERBB3 co-mutations, however all 7 were missense variants (5 of which are p.E928G variants) and occurred among HER2-kinase patients. Conclusions: Real-world data show increased HER2 mRNA expression in both HER2-mut and HER2-amps MBC patients. Co-occurring genomic alterations were different among all three groups. Notably, ERBB3 and CDH1 alterations co-occurred commonly in HER2-mut MBC patients, while ESR1 alterations co-occurred in only 4.8%. All ERBB3 co-mutations occurred with HER2 kinase domain mutations, while CDH1 co-mutations were less prevalent in the HER2-kinase group. Understanding the frequency and spectrum of HER2 mutations in MBC, as well as co-mutations, will help to guide combination treatment strategies and improve the clinical benefit of targeted therapy in HER2-mutated MBC. Citation Format: Whitney L. Hensing, Shana N. Thomas, Sherif El-Refai, Elizabeth Mauer, Cynthia Ma, Ron Bose. Gene expression and mutation profiles in HER2-mutated metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-10.

Abstract OT2-01-06: Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer

Abstract Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is standard-of-care for patients with hormone receptor positive (HR+) HER2- metastatic breast cancer (MBC). Immune modulatory effects of CDK4/6i are well documented preclinically but poorly understood in the clinical setting. Our previous study combining letrozole, palbociclib and pembrolizumab in patients with HR+ MBC (NCT02778685) showed a promising complete response rate of 31%. Dynamic changes in peripheral blood mononuclear cell (PBMC) subpopulations indicated that palbociclib may increase CD8+ TEMRA (terminally differentiated effector memory cells) and CD4+ TEM (effector memory cells) and enable immune activation. The current cohort 3 was designed to study the immune modulatory effect of palbociclib as an immune-priming agent with a biomarker enriched design. Methods: Women with ECOG 0-1, HR+ HER2- MBC, RECIST 1.1 measurable disease, no prior therapy for MBC were enrolled. Patients with endocrine therapy, including aromatase inhibitor +/- ovarian suppression or fulvestrant, were eligible. A palbociclib + ET lead-in design was used, starting on day -28 followed by combination therapy with pembrolizumab added on C1D1. Peripheral blood and tumor biopsy at baseline and on-treatment were collected to allow in-depth analysis of biomarkers predicting response to the combination. The primary endpoint was to evaluate if the palbociclib potentiated immune responses as a “priming” agent through PBMC analysis and on treatment tumor biopsy. Secondary endpoints included other immune cell subsets and changes that follow the combination with pembrolizumab. With 25 patients, assuming a standard deviation of 0.51 in the relative change in classic monocytes in PBMCs, there is 90% power to detect a relative change of log(C1D1/baseline) of 34.5% with a type I error (two-sided) of 0.05. Results: Between August 2020 and April 2022, 16 patients were enrolled in cohort 3. Currently 11 patients have adverse event (AEs) and 16 patients have response data. Median age was 57 years (39-72). 8/11 (73%) were non-Hispanic white, 1/11 (9%) Hispanic, 1/11 (9%) Asian, and 1/11 (9%) African American. 87% patients had grade 3 AEs, and 30% had grade 4 AEs. Grade 3 AEs were 9/11 (82%) neutropenia, 5/11 (45%) leukopenia, 1/11 (9%) elevated LFTs, and 1/11 (9%) each lymphopenia, hot flashes, febrile neutropenia, and pneumonitis. Grade 4 AEs were 1/11 (9%) lymphopenia. 8/16 (50%) patients achieved a partial response (PR), 5/16 (31%) had stable disease (SD), and 1/16 (6%) had progression of disease (PD) by RECIST 1.1. Additionally, 2/16 (13%) patients were too early to determine best overall response. Response rate (CR+PR) was 50%. PBMCs and tumor microenvironment profiling are ongoing. Conclusion: The combination of palbociclib, pembrolizumab and ET is well tolerated, and a response rate of 50% was identified in HR+ MBC patients who received this combination as front-line therapy. Dynamic changes in peripheral blood mononuclear cells and tumor microenvironment profiling are ongoing. Citation Format: Yuan Yuan, Colt A. Egelston, Weihua Guo, Susan E. Yost, Paul H. Frankel, Christopher Ruel, Mireya Murga, Aileen Tang, Norma Martinez, Daniel Schmolze, Daphne Stewart, James Waisman, Kelly Yap, Joanne Mortimer, Niki Tank. Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-06.

Abstract PD13-07: PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-07.

Abstract P4-01-36: Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

Abstract Background: Trastuzumab deruxtecan (T-DXd) improves outcomes in HER2-positive metastatic breast cancer (MBC) patients, including patients with previously treated stable brain metastases (BMs). Our objective was to examine the characteristics of HER2-positive MBC patients with BMs prior to T-DXd use. Methods: We performed a retrospective cross-sectional study of T-DXd prior authorization (PA) approvals by OncoHealth for HER2-positive MBC patients between 1/17/2020 – 6/21/2022. Using medical records and utilization management data, we assessed the characteristics of PA approvals for 145 patients requesting T-DXd in Stage 4, HER2-positive, female MBC with BMs. Results: Brain metastases were identified in 41/145 patients with HER2-positive MBC prior to T-DXd authorization. Among the 41 patients The mean age was within the range of 50-59 years, 72% were hormone receptor-positive, and all were HER2 positive. 19/41(46%) had symptomatic BMs, 5/41(12%) had asymptomatic BMs. Prior local therapies for the BMs included craniotomy in 19.5% and brain radiotherapy in 87.8% prior to T-DXd. The median number of prior MBC therapies was 2 (range: 0-8) and 73% (30/41) did not receive tucatinib-based therapy prior to T-DXd. Tucatinib-based therapy was the most common subsequent line of therapy among T-DXd patients with further therapy (5/8). For available data (13 metastatic patients), 8 metastatic patients received tucatinib for an average of 149 days before receiving T-DXd for an average of 238 days, compared to 5 metastatic patients who received T-DXd for an average of 295 days before receiving tucatinib for 240 days, implying improved disease management in the T-DXd-to-tucatinib sequence. Conclusions: In the real world, patients with symptomatic, progressing BMs are more likely to receive T-DXd prior to tucatinib or potential tucatinib-based therapy, with longer duration of stability and treatment. Appropriate sequencing of available treatments with activity on brain metastases such as T-DXd and tucatinib-based therapy needs to be further studied. Citation Format: Andrew Toler, Laura R. Bobolts, Mark Mangurian, Melissa Pozotrigo, Corey Wise, Hiywete Solomon, Nicole Hartung, Rory Makielski, Shika Marur, Meera Ravindranathan, Shanthi Marur. Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-36.

Polysialic acid-functionalized liposomes for efficient honokiol delivery to inhibit breast cancer growth and metastasis

To improve the anti-metastasis effects of honokiol (HNK) on breast cancer, we designed cationic liposomes (Lip) in which HNK was encapsulated into Lip, and its surface was modified with negatively charged polysialic acid (PSA-Lip-HNK) for efficient treatment of breast cancer. PSA-Lip-HNK possessed a homogeneous spherical shape and high encapsulation efficiency. In vitro 4T1 cell experiments indicated that PSA-Lip-HNK increased cellular uptake and cytotoxicity via the endocytosis pathway mediated by PSA and selectin receptors. Furthermore, the significant antitumor metastasis impact of PSA-Lip-HNK was confirmed by wound healing and cell migration and invasion. Enhanced in vivo tumor accumulation of the PSA-Lip-HNK was observed in 4T1 tumor-bearing mice by living fluorescence imaging. For in vivo antitumor experiments using 4T1 tumor-bearing mice, PSA-Lip-HNK exhibited a higher tumor growth and metastasis inhibition compared with unmodified liposomes. Therefore, we believe that PSA-Lip-HNK well combined biocompatible PSA nano-delivery and chemotherapy, providing a promising drug delivery approach for metastatic breast cancer therapy.

SREKA-targeted liposomes for highly metastatic breast cancer therapy

Chemotherapy is still a leading therapeutic approach in various tumor types that is often accompanied by a poor prognosis because of metastases. PEGylated liposomes with CREKA targeting moiety are well-known therapeutic agents, especially in highly metastatic experimental models. CREKA specifically targets tumor-associated ECM, which is present at the primary, as well as metastatic tumor sites. To better understand the function of the targeting moieties, we decided to design various liposome formulations with different amounts of targeting moiety attached to their DSPE-PEG molecules. Moreover, a new tumor-homing pentapeptide (SREKA) was designed, and a novel conjugation strategy between SREKA and DSPE-PEGs. First, the in vitro proliferation inhibition of drug-loaded liposomes and the cellular uptake of their cargo were investigated. Afterward, liposome stability in murine blood and drug accumulation in different tissues were measured. Furthermore, in vivo tumor growth, and metastasis inhibition potencies of the different liposome formulations were examined. According to our comparative studies, SREKA-liposomes have a uniform phenotype after formulation and have similar characteristics and tumor-homing capabilities to CREKA-liposomes. However, the exchange of the N-terminal cysteine to serine during conjugation results in a higher production yield and better stability upon conjugation to DSPE-PEGs. We also showed that SREKA-liposomes have significant inhibition on primary tumor growth and metastasis incidence; furthermore, increase the survival rate of tumor-bearing mice. Besides, we provide evidence that the amount of targeting moiety attached to DSPE-PEGs is largely responsible for the stability of liposomes, therefore it plays an important role in toxicity and targeting.

P38 Mitogen-Activated Protein Kinase Signaling Enhances Reovirus Replication by Facilitating Efficient Virus Entry, Capsid Uncoating, and Postuncoating Steps.

Mammalian orthoreovirus serotype 3 Dearing is an oncolytic virus currently undergoing multiple clinical trials as a potential cancer therapy. Previous clinical trials have emphasized the importance of prescreening patients for prognostic markers to improve therapeutic success. However, only generic cancer markers such as epidermal growth factor receptor (EGFR), Hras, Kras, Nras, Braf, and p53 are currently utilized, with limited benefit in predicting therapeutic efficacy. This study aimed to investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling during reovirus infection. Using a panel of specific p38 MAPK inhibitors and an inactive inhibitor analogue, p38 MAPK signaling was found to be essential for establishment of reovirus infection by enhancing reovirus endocytosis, facilitating efficient reovirus uncoating at the endo-lysosomal stage, and augmenting postuncoating replication steps. Using a broad panel of human breast cancer cell lines, susceptibility to reovirus infection corresponded with virus binding and uncoating efficiency, which strongly correlated with status of the p38β isoform. Together, results suggest p38β isoform as a potential prognostic marker for early stages of reovirus infection that are crucial to successful reovirus infection. IMPORTANCE The use of Pelareorep (mammalian orthoreovirus) as a therapy for metastatic breast cancer has shown promising results in recent clinical trials. However, the selection of prognostic markers to stratify patients has had limited success due to the fact that these markers are upstream receptors and signaling pathways that are present in a high percentage of cancers. This study demonstrates that the mechanism of action of p38 MAPK signaling plays a key role in establishment of reovirus infection at both early entry and late replication steps. Using a panel of breast cancer cell lines, we found that the expression levels of the MAPK11 (p38β) isoform are a strong determinant of reovirus uncoating and infection establishment. Our findings suggest that selecting prognostic markers that target key steps in reovirus replication may improve patient stratification during oncolytic reovirus therapy.

Smart Chondroitin Sulfate Micelles for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Metastasis.

Metastasis is a major challenge in breast cancer therapy. The successful chemotherapy of breast cancer largely depends on the ability to block the metastatic process. Herein, we designed a dual-targeting and stimuli-responsive drug delivery system for targeted drug delivery against breast cancer metastasis. AS1411 aptamer-modified chondroitin sulfate A-ss-deoxycholic acid (ACSSD) was synthesized, and the unmodified CSSD was used as the control. Chemotherapeutic drug doxorubicin (DOX)-containing ACSSD (D-ACSSD) micelles were prepared by a dialysis method. The ACSSD conjugate was confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). In vitro cellular uptake and cytotoxicity of D-ACSSD micelles were studied by confocal laser scanning microscopy (CLSM) and MTT assay in breast tumor cells. The inhibition capability of D-ACSSD micelles in cell migration and invasion was carried out in 4T1 cells. In vivo antitumor activity of DOX-containing micelles was investigated in metastatic 4T1-bearing Balb/c mice. D-ACSSD and DOX-loaded CSSD (D-CSSD) micelles exhibited high drug encapsulation content and reduction-responsive characteristics. D-ACSSD micelles were spherical in shape. Compared with D-CSSD, D-ACSSD showed higher cellular uptake and more potent killing activity in 4T1 and MDA-MB-231 cells. Additionally, D-ACSSD exhibited stronger inhibitory effects on the invasion and migration of highly metastatic 4T1 cells than unmodified D-CSSD. Among the DOX-containing formulations, D-ACSSD micelles presented the most effective inhibition of tumor growth and lung metastasis in orthotopic 4T1-bearing mice in vivo. It also revealed that ACSSD micelles did not exhibit obvious systemic toxicity. The smart D-ACSSD micelles could be a promising delivery system for the therapy of metastatic breast cancer.

Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China

BackgroundReal-world data of Palbociclib are insufficient in China. This study aimed to investigate the treatment pattern and real-world outcomes in hormone receptor positive and human epidermal growth factor 2 receptor negative (HR+/HER2-) metastatic breast cancer (MBC) patients treated with Palbociclib in the northwest of China.MethodsHR+/HER2- MBC patients who received Palbociclib in 8 centers from July 2017 to September 2019 were retrospectively included in this study. Real-world objective response rate (ORR), progression-free survival (PFS) and safety profiles were analyzed. The survival curves were plotted by the Kaplan-Meier method to analyze PFS, which was verified by the log-rank test.ResultsIn total, 211 women were eligible for the analysis. A total of 85 patients (40.3%), 78 (37.0%), and 48 (22.7%) received Palbociclib in the first-, second-, third- or later-line setting, respectively. 46 patients achieved partial response and 145 patients experienced stable disease, with an ORR of 21.8% and a disease control rate of 90.5%. Following a median follow-up period of 14.2 months, the median PFS was 12.2 months (95% confidence interval, 10.1-14.3 m), and the median overall survival was not reached. Early Palbociclib initiation, sensitivity or acquired resistance to endocrine therapy, estrogen receptor and progesterone receptor double positivity, less than 3 metastatic sites, without visceral metastasis, bone metastasis only, without prior chemotherapy or endocrine therapy were associated with a prolonged PFS in MBC (All P < 0.05). The most common grade 3 or 4 adverse events (AE) was neutropenia (36.5%), and the most common nonhematologic AE was fatigue (10.9%). No patient experienced AE leading to treatment discontinuation.ConclusionPalbociclib plus endocrine therapy exhibited favorable effectiveness and manageable toxicities in the real-world setting, supporting their use in Chinese patients with HR+/HER2 − MBC.

Erratum to "Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer".

Erratum to "Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer".