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Background: Evidence-based recommendations for the management of metastatic breast cancer (MBC) endorse confirmation of recurrence with biopsy and reassessment of biomarker status. National guidelines support numerous treatment options and do not capture the nuances of real-world practice. Real world data may demonstrate disparities in adherence to guidelines. Methods: We collaborated with Hutchinson Institute for Cancer Outcomes Research (HICOR) to link enrollment and insurance claims records with Washington State cancer registries from 2008-2017. Our cohort comprised of women > 18 years old with MBC who met enrollment criteria in one of four payors (Premara, Regence, Medicare, or Medicaid). We identified receipt of biopsy and biomarker re-assessment at time of recurrence, receipt of first line treatment, categorized as CDK4/6 inhibitors (CDKi), chemotherapy (CT), or hormone therapy (HT) and examined factors influencing these practice patterns. Results: We identified 1,101 patients with MBC (recurrent MBC, N = 715; de novo MBC, N = 386) with a median age of 66 (range 54 – 74). Of the patients with MBC, there were a total of 677 patients with ER+/HER2- MBC. Table 1 shows demographic data. Most of the cohort were White (89%). Approximately 15% of patients lived in areas of high deprivation (area of deprivation index, ADI, 8-10). Patients had either Commercial (47%), Medicaid (4%), Medicare (35%) or multiple (13%) insurance. Of the patients with recurrent MBC, 49.5% received a biopsy to confirm metastatic diagnosis. Similarly, 48.7% of recurrent MBC patients underwent biomarker reassessment. Patients with highest co-morbidity index (2) were more likely to undergo biopsy confirmation (20.3% vs 13.0%, p = 0.02). Biopsy was more often performed at recurrence in patients receiving care at a high-volume center (74.3% vs 67.6%, p = 0.03) compared to low volume center (18.6% vs 26.6%, p = 0.03). First line treatment selection was directly associated with receipt of biopsy and biomarker testing. Hormone therapy only was more common in patients who did not undergo biopsy (62.3% vs 37.7%, p < 0.001) or biomarker reassessment (62.7% vs 37.3%, p < 0.001). Of the patients with ER+/HER2- MBC, the majority of patients received ET alone (69%), followed by chemotherapy (22%), and CDK4/6i + ET (9%). Dual agent CT was the more commonly prescribed compared to single agent in those who received CT (56% vs 44%). The majority of patients who received CDKi + ET were < 65 years old (65.2%, p < 0.02). Insurance influenced first line therapy selection and patients with commercial insurance were more likely to receive CDK4/6i + ET compared to those with Medicare/Medicaid. (60.9% vs 26.1%, p = 0.10). Patients with de novo MBC were more likely to receive CT (43.1% vs 13.4%, p < 0.001) and less likely to receive ET alone (47.9% vs 78.0%, p < 0.001). Almost all patients treated with CDK4/6i + ET received care a high-volume center (91.3%, p = 0.11). Conclusion:Our findings highlight key gaps for future investigations in the management of MBC and serve as a launching point for new patient-centered and quality-promoting research initiatives. Table 1: Baseline Demographics 1# of patients treated annually, high = >100, medium 25-100, low Citation Format: Poorni Manohar, Hannah Linden, Veena Shankaran, Catherine Fedorenko, Jenna Voutsinas, Qin Sun, Vicky Wu. Real-world practice patterns in the management of metastatic breast cancer in Washington State [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 P4-07-47.

FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols BACKGROUND: Genomic signatures, such as the 70-gene MammaPrint, provide additional prognostic information for early-stage breast cancer (EBC), such as tumor metastatic potential, and expand the available information clinicians and patients require for shared treatment decision making beyond the standard clinicopathologic factors. EBC tumors are further stratified into clinically actionable subtypes by molecular assays such as the 80-gene molecular profiling assay BluePrint, improving pathological complete response rates (pCR) and outcomes as evidenced by a number of recent trials. The ongoing FLEX Study (NCT03053193) is designed to expand the genomic information available for EBC cases, and to increase the speed of data generation for rare and underserved research areas. To date, FLEX is the largest international multicenter real-world evidence (RWE) EBC registry, with more than 10,000 patients enrolled in fewer than five years since opening. FLEX pairs full genome data with more than 800 clinical data points collected over 10 years of follow up to provide the most comprehensive big data database available for early-stage breast cancer. The FLEX enrollment has a goal of a minimum of 30,000 patients within 10 years. METHODS: The FLEX study is a multicenter, prospective, observational trial for patients ≥18 years old with histologically proven stage I-III invasive breast cancer that is node negative or positive (up to three nodes) who receive MammaPrint, with or without BluePrint as standard of care management. Patients consent to the collection of clinically annotated full transcriptome data. Additionally, this study protocol allows physicians to investigate targeted populations or clinical trial investigator-initiated studies (IIS) upon approval by a peer-driven Scientific Review Committee. As patients enrolled in the FLEX study meet all eligibility criteria for inclusion no additional consent is required. The FLEX enrollment has already surpassed 1/3 of set target goal. As of April 2022, the trial has surpassed 10,000 patients enrolled at nearly 100 trial sites across the US and Europe, Middle East and Africa (EMEA). To date, there have been 36 publications in international scientific congresses with 39 FLEX IIS and in progress. With over 250 active and collaborating physicians leveraging the shared infrastructure, the IIS have enabled the ability to address disparities in treatment to underrepresented populations, rare subtypes, age, and patient centered specific topics. Current and future questions investigated via this platform will continue to strive to improve outcomes for early-stage breast cancer patients. Citation Format: Alejandra Perez, Hannah Linden, Nathalie Johnson, Sami Diab, Chirag Jani, Chelsea D. Gawryletz, Richard Fine, Laura Lawson, Megan Baker, Victoria Poillucci, Lisa E. Blumencranz, William Audeh. FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols [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 OT2-05-01.

To compare the outcome of allogeneic stem cell transplantation for myeloid malignancies in breast cancer survivors to a contemporaneous control group.Medical records of all patients with a history of breast cancer who received allogeneic stem cell transplants at a single, tertiary referral Comprehensive Cancer Center between 2002 and 2019 were reviewed. Transplant outcomes were compared to 289 control patients without a history of breast cancer from the same time period. Main outcomes included survival, disease-free survival, non-relapse mortality, relapse or progression of hematologic malignancy, and incidence of recurrent breast cancer after hematopoietic cell transplantation. Comparisons between women with a history of breast cancer and controls utilized propensity score weighting to balance patient characteristics.Forty women, ages 30-74 years, with a history of breast cancer received an allogeneic hematopoietic cell transplant for a hematologic malignancy between December 2002 and February 2019. Twelve of the 40 patients are alive with a median survival of 7.4 years (range, 1.9-16.8 years). None of the patients had evidence of recurrent breast cancer prior to death or date of last contact. In multivariable Cox models, all transplant outcomes were similar between the patients and the control group with hematopoietic cell transplant comorbidity score as the most important confounding factor for adjustment in these models.A history of treated breast cancer should not exclude patients from consideration for allogeneic hematopoietic cell transplantation.

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.Experimental Design: We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28).Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.

CCR Translation for This Article from HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

Background Endocrine therapy in combination with a targeted cyclin-dependent kinase (CDK) 4/6 inhibitor is the clinical standard for treatment of ER+/HER2- advanced breast cancer. Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. In previous arms of the AMEERA-1 study, amcenestrant, as monotherapy or in combination with the CDK4/6 inhibitor palbociclib, demonstrated antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. The objective of Arm 5 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the CDK4/6 inhibitor abemaciclib for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 5 investigates dose escalation (Part J) and dose expansion (Part K), of amcenestrant in combination with abemaciclib. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 5 (Parts J and K), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Prior treatment with fulvestrant or any other SERD is not allowed; in addition, prior therapy with CDK4/6 inhibitors for advanced disease is not allowed. Part J allows ≤ 1 prior chemotherapy for advanced disease, while prior chemotherapy for advanced disease is not allowed in Part K. Additional exclusion criteria in Arm 5 are prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; and history of or concurrent venous thromboembolism (i.e., deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis). Part J evaluates the selected amcenestrant dose for combination therapy plus abemaciclib 150 mg twice daily (BID) (the approved standard dose) or abemaciclib 100 mg BID, taken in 28-day cycles. Additional dose levels of amcenestrant may be explored based on safety and pharmacokinetics (PK). The objective of Part J is to determine the recommended dose (RD) of abemaciclib in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part J is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of abemaciclib in combination with amcenestrant in Part J. In Part K, approximately 20 patients will be treated at the RD of abemaciclib for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Sarat Chandarlapaty, Aditya Bardia, Patrick Neven, Katarina Petrakova, Peter Kabos, Valentina Boni, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Hannah Linden. Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced 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 OT2-11-04.

Targeting the androgen receptor (AR) may be the next important endocrine therapy for women with advanced breast cancer. AR is the most abundantly expressed steroid receptor in breast cancer and has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective nonsteroidal agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials and 1,450 dosed subjects including in breast cancer where three Phase 2 studies have been conducted two of which were in women (158 subjects) who had AR+/ER+/HER2- metastatic breast cancer (MBC).The larger Phase 2 clinical trial (G200802) evaluated 9mg and 18mg enobosarm daily oral dosing in 136 women with ER+/HER2- MBC who previously responded to endocrine treatment. Patients were heavily pretreated having progressed on an average of 3 endocrine treatments and 90% had prior chemotherapy. Enobosarm showed efficacy activity in the overall study with a clinical benefit rate at 6 months of 32% (95% CI: 19.5%,46.7%) for the 9 mg and 29% (95% CI: 17.1%,43.1%) for the 18 mg evaluable cohorts. Quality of life assessments showed significant improvement from baseline for both enobosarm cohorts (p=0.002). Enobosarm was well tolerated at both doses. In a post-hoc analysis in all patients (9mg and 18mg) with known AR status and measurable disease (n=84), AR expression in breast. cancer tissue (%AR nuclei staining) correlated with efficacy outcomes. When comparing AR nuclei staining ≥40% (n=47) compared to patients with an AR nuclei staining Citation Format: Adam Brufsky, Hannah Linden, Hope Rugo, Charles Vogel, Joyce A O'Shaughnessy, Robert H Getzenberg, K. Gary Barnette, Domingo Rodriguez, Mitchell S Steiner, Erica Mayer. Randomized, multicenter, international phase 3 ARTEST study to evaluate the efficacy and safety of enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who progressed on a nonsteroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor [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 OT2-17-01.

Background: 18F-Fluorodeoxyglucose (FDG) has long been used for measuring tumor glycolytic activity in clinical PET imaging. The FDA recently approved 18F-Fluoroestradiol (FES) (Cerianna) as a PET imaging tracer for characterizing disease in patients with estrogen-receptor positive (ER+) breast cancer. As FES PET enters clinical practice it is important to establish its utility in the full population of hormone-receptor positive patients, including for patients with human epidermal growth factor 2 (HER2)-overexpressing tumors. Patients with HER2-positive metastatic breast cancer have historically been treated with combination cytotoxic and HER2-directed therapy, with the understanding that HER2 is the primary driver in this disease state. This retrospective study examined uptake in matched lesions for both FES and FDG PET and compared activity in patients with HER2 positive versus HER2 negative metastatic breast cancer. Methods: Patients were selected from the UW research database who had a history of biopsy-proven primary ER+ breast cancer as well as FES and FDG PET scans within 30 days. We examined FDG and FES scans and recorded SUVmax in up to 16 matched lesions between the two scans. Patients were also divided by HER2 status (+/-). In addition, a subset of patients who underwent at least 2 paired FDG and FES scans were reviewed. Results: 270 matched FDG and FES scans were analyzed in 216 patients with history of ER+, and HER2+ or HER2- breast cancer who were not part of an ongoing clinical trial. 158 (73%) had ductal disease, 38 (18%) had lobular disease. 183 (85%) had HER2- breast cancer. Of the 33 patients who had HER2+ breast cancer, 28 (85%) had ductal carcinoma. 40 patients underwent serial scans, allowing tracking over multiple timepoints. A total of 1323 metastatic sites were recorded (average = 5/scan (range 1,16)), with the majority (71%) representing bony lesions. No difference in quantitative FES or FDG avidity was observed between soft tissue and osseous sites. FES and FDG SUVmax were similar among patients with either HER2- or HER2+ breast cancer (Table 1). Among 40 patients with multiple paired FDG and FES scans, 26 (65%) had 2 scans while the remaining 14 had 3, with FES avidity remaining stable over time. There was no correlation between FES or FDG scans and HER2 status. Conclusion: In a cohort of ER+, HER2+ and HER2- patients undergoing concurrent FDG and FES PET scans, FDG and FES activity was similar regardless of HER2 status. FES uptake in both HER2- and HER2+ patients and stability over time in serial scans suggest that HER2 does not affect ER density. This suggests that in many patients with so-called “triple positive” disease, endocrine therapy may offer a powerful primary rather than ancillary tool in select patients. FES combined with FDG PET may offer utility in predicting and assessing response to therapy in this patient population. Table 1. FES and FDG uptake in patients with HER2- or HER2+ disease Citation Format: Natasha Hunter, Lanell M. Peterson, David A. Mankoff, Mark Muzi, Delphine Chen, William R. Gwin, Shaveta Vinayak, Nancy E Davidson, Jennifer M. Specht, Hannah Linden. Fluoroestradiol (FES) and Fluorodeoxyglucose (FDG) PET imaging in patients with ER+, HER2+ or HER2- 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 P2-03-17.

Background: 18F-FES is an FDA-approved estrogen analogue PET imaging tracer (Cerianna) which measures tumor estrogen receptor (ER) expression at multiple tumor sites simultaneously and predicts response to endocrine therapy. 18F-FDG is a commonly used glucose PET imaging tracer which measures glycolytic metabolic activity in tumors. Elevated plasma ctDNA has been associated with an increased risk of relapse and can identify actionable genomic alterations. This pilot research study explored the relationship between somatic copy-number variants (CNVs) and cell-free DNA mass using low-pass-whole-genome (LPWG) ctDNA in the blood to FES and FDG PET/CT findings with both qualitative and quantitative image analysis in metastatic breast cancer patients. Methods: Two(2) 10ml Streck tubes were collected from 20 patients with metastatic ER+ breast cancer +/-30 days of their FDG-PET/CT scan (n=19) or their FES-PET/CT scan (n=9). 8 patients had both scans. Somatic mutations were assessed using comprehensive genomic profiling of tissue samples from 19 patients using the clinically validated UW-Oncoplex assay. Qualitative analysis included detection of LPWG ctDNA, presence of PIK3A mutations in tissue, and intensity of uptake in PET/CT imaging. LPWG ctDNA of blood samples evaluated ctDNA mass and CNVs that comprised at least 8% of total ctDNA. Total lesion glycolysis (TLG) in FDG scans and total lesion estrogen receptors (TLER) in FES scans were calculated using a dedicated workflow in MiM software (MiM Software Inc. Cleveland OH). Quantitative analysis included the circulating fraction (ctDNA), PET/CT SUVmax of the index lesion, number of lesions, TLG and TLER. For TLG, the threshold for determining measurable lesions was calculated using liver SULmean + 1.5*SD. The threshold for TLER was calculated using SUVmean of the mediastinal blood pool. The ctDNA fraction and the number of lesions for both FDG and FES were each ranked into 3 categories. FDG and FES data (SUVmax of index lesion, # of lesions, and TLG or TLER) were correlated to the calculated ctDNA fraction values. TLG and TLER were also correlated to each other. Results: ctDNA was classified as no ctDNA present (n=9), ctDNA present (n=8) and indeterminate (n=3). Average neoplastic ctDNA fraction was 0.114 (range 0.03-0.423). PIKC3A mutations were: 10 absent and 9 present. Ranked categories for ctDNA fraction, FDG TLG and FES TLER are shown in Table 1. Table 2 shows results of FDG and FES analysis and correlation with ctDNA. Ranked ctDNA findings correlated with both the FDG number of lesions (R2=0.69) and TLG (R2=0.83), but not the SUVmax of the index lesion (R2=0.29). Correlation decreased for ctDNA versus FES number of lesions (R2=0.51), TLER (R2=0.61), and SUVmax of index lesion (R2=0.16). TLG and TLER significantly correlated with the 8 patients that had both an FDG and FES PET/CT scan (R2=0.77). Conclusions: In this pilot study, FDG TLG showed a significant correlation with ctDNA. There is an encouraging association with ctDNA fraction and number of FDG lesions and with ctDNA fraction and extent of FES avid disease (TLER) in the 9 patients that had FES. Research Support: RG1005258 Table 1. Categorical rankings for qualitative analysis of ctDNA, TLG and TLER Table 2. FDG and FES imaging results and correlation with ctDNA Citation Format: Natasha Hunter, Lanell M. Peterson, Mark Muzi, Eric Q. Konnick, Jonathan Reichel, Paul Kinahan, Jennifer M. Specht, Rachel Yung, William R. Gwin, Hannah Linden, Christina Tran. Pilot study to evaluate circulating tumor DNA (ctDNA) to PET/CT imaging using 18F-Fluorodeoxyglucose (FDG) and 18F-Fluoroestradiol (FES) PET/CT imaging as biomarkers in patients with 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 P2-03-25.

Although patients with cancer often face serious financial hardships, few studies have reported on strategies to mitigate this burden. Improving literacy about the financial aspects of cancer care may decrease the negative financial impact of cancer diagnosis and treatment. We obtained input from patient stakeholders on the perceived value and optimal design of a financial literacy program in the advanced cancer setting.Prospective cohort survey.A series of semi-structured interviews were conducted, during which patients with either colorectal or breast cancer were asked to describe the impact of cancer on their finances and employment, to state their preferences about discussing costs with their providers, and to give input on development of a financial literacy course.Twenty-one patients (76% Caucasian) completed interviews, the majority of whom had Medicare or commercial insurance (71%). Lost income from early retirement or disability was the most financially burdensome experience for 67% of patients. The majority of patients (76%) reported that a financial literacy course would be helpful in navigating the cost of cancer care. Most preferred the course be administered at diagnosis in a live group format.Feedback from patients with cancer supported the development of a group financial literacy course that addresses barriers to discussing cost concerns, employment changes during cancer, and available resources for financial assistance.

We sought to determine the prevalence of androgen receptor (AR) expression in a predominantly estrogen receptor (ER)-negative subset of breast cancers and delineate the immunohistochemical and clinical associations, including whether AR expression has prognostic significance in ER-negative tumors. We identified 69 ER-negative and 19 ER-positive breast cancer cases with concurrent immunohistochemical prognostic panels (ER, PR, HER-2/neu, Ki-67, and p53); immunohistochemical analysis was performed for AR using standard techniques. Clinical data were extracted from medical records. chi 2 tests were used to assess associations between variables. AR was found in 49% (34/69) of ER-negative and 89% (17/19) of ER-positive cases. In ER-negative tumors, AR was associated with increased age (P = .02), postmenopausal status (P.001), tumor grade (P = .03), tumor size (P = .03), and HER-2/neu overexpression (P = .003). In ER-positive tumors, AR was associated with progesterone receptor expression (P.03). In univariate analysis of ER-negative tumors, patients with AR-positive tumors had significantly better disease-free survival (P = .049). AR is expressed in a significant number of ER-negative cases and shows significant associations with important clinical and pathologic prognostic factors.