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Purpose: To investigate the relationship between changes in vascularity and metabolic activity measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and dynamic (18)F-FDG-positron emission tomography (PET) in breast tumors undergoing neoadjuvant chemotherapy.Materials and Methods: PET and MRI examinations were performed in 14 patients with locally advanced breast cancer (LABC) before and after chemotherapy. Dynamic (18)F-FDG PET measures included (18)F-FDG transport rate constant from blood to tissue (K(1)) and metabolism flux constant (Ki). DCE-MRI measures included initial peak enhancement (PE), signal enhancement ratio (SER), and tumor volume. Spearman rank-order correlations were assessed between changes in PET and MRI parameters, and measures were compared between patients with and without pathologic complete response (pCR) by Mann-Whitney U-test.Results: Changes in glucose delivery (PET K(1)) were closely correlated with changes in tumor vascularity as reflected by DCE-MRI SER (r = 0.83, P < 0.001). Metabolic changes in PET Ki showed moderate correlations with vascularity changes as reflected by SER (r = 0.71) and PE (r = 0.76), and correlated closely with MRI tumor volume (r = 0.79, P < 0.001). Decreases in K(1), Ki, SER, and PE were greater for patients with pCR compared to those with residual disease (P < 0.05).Conclusion: Dynamic (18)F-FDG PET and DCE-MRI tumor measures of tumor metabolism, vascularity, and volume were well correlated for assessing LABC response to neoadjuvant chemotherapy and significantly discriminated pathologic complete responders. Further work is necessary to assess the value of combined PET and MRI for evaluating tumor pharmacodynamics in response to novel therapy. [ABSTRACT FROM AUTHOR]

Purpose: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells., Patients & Methods: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion., Results: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1., Conclusion: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20μL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue., Competing Interests: All authors have read and understand PLOS ONE’s policies. The below commercial interests did not fund and have no association with the work performed in this study; therefore, this does not alter our adherence to PLOS ONE’s policies on sharing data and materials. The authors of this manuscript have the following competing interests: A.G.C. received research funding from Juno Therapeutics, a Bristol Myers Squibb Company. E.K. received research funding from Juno Therapeutics, a Bristol Myers Squibb Company. A.V.H. has received research funding from Juno Therapeutics, a Bristol Myers Squibb Company, and Nektar Therapeutics; has received honoraria from Bristol Myers Squibb. C.J.T. has received research funding from Juno Therapeutics/BMS, Nektar Therapeutics. C.J.T. is on the scientific advisory board for Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Celgene/BMS Cell Therapy. C.J.T. is a DSMB member for Kyverna. C.J.T. ad hoc advisory boards/consulting (last 12 months) include: Nektar Therapeutics, Century Therapeutics, Legend Biotech, Allogene, Sobi, Syncopation Life Sciences, Prescient Therapeutics, Orna Therapeutics, IGM Biosciences, Abbvie. C.J.T. stock options: Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics. C.J.T. has the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy C.Y. has received research funding from Minerva, Lonza. C.Y. consults for TwinStrand Biosciences., (Copyright: © 2024 Pullarkat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As the proportion of women diagnosed with invasive breast cancer increases, the role of imaging for staging and surveillance purposes should be determined based on evidence-based guidelines. It is important to understand the indications for extent of disease evaluation and staging, as unnecessary imaging can delay care and even result in adverse outcomes. In asymptomatic patients that received treatment for curative intent, there is no role for imaging to screen for distant recurrence. Routine surveillance with an annual 2-D mammogram and/or tomosynthesis is recommended to detect an in-breast recurrence or a new primary breast cancer in women with a history of breast cancer, and MRI is increasingly used as an additional screening tool in this population, especially in women with dense breasts. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein., Methods: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032., Findings: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event., Interpretation: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile., Funding: Pfizer and Celcuity., Competing Interests: Declaration of interests RML received medical writing support and institutional research funding from Celcuity and Pfizer; institutional research funding from Novartis, Eli Lilly, Puma, Zentalis, Arvinas, and Accutar Biotechnology; and consulting fees from or participation on advisory boards for Celcuity, Pfizer, Novartis, Eli Lilly, Gilead, and Biotheryx. HSH received institutional research funding from Abbvie, Arvinas, Celcuity, Department of Defense, G1 Therapeutics, GlaxoSmith Kline, Horizon Oncology Research, Marker Therapeutics, Mersana, Novartis, Pfizer, Phoenix Pharmaceuticals, Pyonr, QuantumLeap Health, and Seagen, Zymeworks; consulting fees from or participation on advisory boards for Daiichi Sankyo–Astra Zeneca, Immunomedics–Gilead, and Novartis; and Speaker's Bureau fees for Eli Lilly. HSR received institutional research funding from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F Hoffmann-La Roche–Genentech, Gilead Sciences, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr; consulting fees from or participation on advisory boards for Napo Pharmaceutical, Puma Biotechnology, Blueprint, Scorpion Therapeutics, and Daiichi Sankyo; and honoraria from Blueprint, Mylan, and Puma Biotechnology. EMS-R received research funding from Susan G Komen, V Foundation, NIH, and Breast Cancer Research Foundation; consulting fees from or participation on advisory boards for Lilly, SeaGen, Immunomedics, Tersera, AstraZeneca, Merck, Novartis, and Mylan; other payments or honoraria from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, American Association for Cancer Research–Bristol Myers Squibb–Winn Clinical Trials Workshop. JMS received institutional research funding from Celcuity, Pfizer, Merck, Seagen, Seattle Genetics, Minerva, Myriad Pharmaceuticals, Novartis, Genentech, Cascadian Therapeutics, Abbvie, and Nektar; consulting fees from Volastra and GE Healthcare; royalties or licenses from UW Comotion as a donation to the UW Breast Program; honoraria from Binaytara Foundation, Washington State Medical Oncology Society, and Hong Kong International Oncology Symposium; meeting or travel support from ECOG ACRIN, A2 Biotherapeutics, IwCAR-T, the Society of Nuclear Medicine and Molecular Imaging, and Translational Breast Cancer Research Consortium; and is a member of data safety monitoring or advisory boards for GE Healthcare, Sensei Biotherapeutics, and GlaxoSmithKline. ECD received institutional research funding from Merck, Novartis, Meryx, H3 Biomedicine, and G1 Therapeutics and participated on the data safety monitoring board for Sanofi. PK received institutional research funding from AstraZeneca, Hibercell, Sanofi, Eli Lilly, Zymeworks, and Genentech. SS is a full-time employee of Celcuity receiving a salary and holding shares in Celcuity; and received consulting fees from Celcuity (before employment), Artiva Biotherapeutics, Elevation Oncology, Kartos Therapeutics, Tellios Pharma, and Direct Biologics. SCM, BFS, and IG are full-time employees of Celcuity receiving a salary and holding shares in Celcuity. RW received institutional research funding from Celcuity and Pfizer, is a member of advisory boards for Celcuity and Seagen, and is a member of the investigational steering committee for this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose ( 18 F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases., Methods: For this study, nine patients with 38 bone lesions were imaged with 18 F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18 F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18 F-FDG before and after standard-of-care therapy for response assessment., Results: The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and - 16.3% for SUVmax, and 21.2% and - 17.5% for SULpeak. 18 F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak., Conclusion: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18 F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18 F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response., (© 2024. The Author(s).)

Objectives: Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment., Methods: Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as "one primary only." Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival., Results: Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period ( P =0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P <0.001) and 23% received chemotherapy (vs. 45% for PBA, P =0.11)., Conclusions: We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma., Competing Interests: E.T.L.—Clinical trial funding from BioAtla, Ayala, and SpringWorks. L.D.C.—Clinical trial funding from Eli Lilly, AADi, BluePrint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma. Honoraria or has served on advisory boards for Daaichi Sankyo. M.J.W.—Clinical trial support from Deciphera, Adaptimmune, GSK, Athenex, Foghorn Therapeutics, Shaqsi, Presage Biosciences, Inhibrx, and Incyte. Consulting fees from Adaptimmune, Epizyme, Aadi, and Deciphera. H.M.L.—Research funding from Tolmar, EliLilly, GE Healthcare, Sanofi, and Zymeworks. Consulting for GE Healthcare, Novartis, Sanofi, and Eli Lilly. J.M.S.—Research funding from Celcuity, Genentech, Xencor, Pfizer, SeaGen, Merck, Carisma, and Lyell. Consultant/advisory boards: A2 Biotherapeutics, Volastra Therapeutics, GE Healthcare, Sensei Therapeutics, and GlaxoSmithKline. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate combined MRI and 18 F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer., Methods: Patients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18 F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K 1 ) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated., Results: Thirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31-66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18 F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18 F-FDG PET (K 1 ) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS., Conclusion: Mid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18 F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome., (© 2023. The Author(s).)

Objective: When multiple surveillance mammograms are performed within an annual interval, the current guidance for one-year follow-up to determine breast cancer status results in shared follow-up periods in which a single breast cancer diagnosis can be attributed to multiple preceding examinations, posing a challenge for standardized performance assessment. We assessed the impact of using follow-up periods that eliminate the artifactual inflation of second breast cancer diagnoses., Materials and Methods: We evaluated surveillance mammograms from 2007-2016 in women with treated breast cancer linked with tumor registry and pathology outcomes. Second breast cancers included ductal carcinoma in situ or invasive breast cancer diagnosed during one-year follow-up. The cancer detection rate, interval cancer rate, sensitivity, and specificity were compared using different follow-up periods: standard one-year follow-up per the American College of Radiology versus follow-up that was shortened at the next surveillance mammogram if less than one year (truncated follow-up). Performance measures were calculated overall and by indication (screening, evaluation for breast problem, and short interval follow-up)., Results: Of 117971 surveillance mammograms, 20% (n = 23533) were followed by another surveillance mammogram within one year. Standard follow-up identified 1597 mammograms that were associated with second breast cancers. With truncated follow-up, the breast cancer status of 179 mammograms (11.2%) was revised, resulting in 1418 mammograms associated with unique second breast cancers. The interval cancer rate decreased with truncated versus standard follow-up (3.6 versus 4.9 per 1000 mammograms, respectively), with a difference (95% confidence interval [CI]) of -1.3 (-1.6, -1.1). The overall sensitivity increased to 70.4% from 63.7%, for the truncated versus standard follow-up, with a difference (95% CI) of 6.6% (5.6%, 7.7%). The specificity remained stable at 98.1%., Conclusion: Truncated follow-up, if less than one year to the next surveillance mammogram, enabled second breast cancers to be associated with a single preceding mammogram and resulted in more accurate estimates of diagnostic performance for national benchmarks., Competing Interests: The authors have no potential conflicts of interest related to this study to disclose. Potential conflicts of interest unrelated to this study: Janie M. Lee grant from GE Healthcare; Jennifer M. Specht payment to author for consultancies from Daiichii Sankyo, GE Healthcare, GSK-Glaxosmithkline; grants from Merck, Cascadian Therapeutics, Pfizer, Genentech, Xencor, Abbvie, Seattle Genetics, Celcuity Inc; Karla Kerlikowske unpaid consultant to Grail for STRIVE study; Diana L. Miglioretti royalties from Elsevier; Kathryn P. Lowry grants from GE Healthcare; and Diana S. M. Buist payment for participation in review activities from Women Informed to Screen Depending on Measures of Risk Data Safety and Monitoring Board. All other authors declare no conflict of interest., (Copyright © 2023 The Korean Society of Radiology.)

Background: In women with previously treated breast cancer, occurrence and timing of second breast cancers have implications for surveillance. The authors examined the timing of second breast cancers by primary cancer estrogen receptor (ER) status in the Breast Cancer Surveillance Consortium., Methods: Women who were diagnosed with American Joint Commission on Cancer stage I-III breast cancer were identified within six Breast Cancer Surveillance Consortium registries from 2000 to 2017. Characteristics collected at primary breast cancer diagnosis included demographics, ER status, and treatment. Second breast cancer events included subsequent ipsilateral or contralateral breast cancers diagnosed >6 months after primary diagnosis. The authors examined cumulative incidence and second breast cancer rates by primary cancer ER status during 1-5 versus 6-10 years after diagnosis., Results: At 10 years, the cumulative second breast cancer incidence was 11.8% (95% confidence interval [CI], 10.7%-13.1%) for women with ER-negative disease and 7.5% (95% CI, 7.0%-8.0%) for those with ER-positive disease. Women with ER-negative cancer had higher second breast cancer rates than those with ER-positive cancer during the first 5 years of follow-up (16.0 per 1000 person-years [PY]; 95% CI, 14.2-17.9 per 1000 PY; vs. 7.8 per 1000 PY; 95% CI, 7.3-8.4 per 1000 PY, respectively). After 5 years, second breast cancer rates were similar for women with ER-negative versus ER-positive breast cancer (12.1 per 1000 PY; 95% CI, 9.9-14.7; vs. 9.3 per 1000 PY; 95% CI, 8.4-10.3 per 1000 PY, respectively)., Conclusions: ER-negative primary breast cancers are associated with a higher risk of second breast cancers than ER-positive cancers during the first 5 years after diagnosis. Further study is needed to examine the potential benefit of more intensive surveillance targeting these women in the early postdiagnosis period., (© 2023 American Cancer Society.)

In the past 5 years, the treatment options available to patients with HER2+ breast cancer brain metastasis (BCBM) have expanded. The longer survival of patients with HER2+ BCBM renders understanding the toxicities of local therapies even more important to consider. After reviewing the available literature for HER2 targeted systemic therapies as well as local therapies, we present a simplified algorithm for when to prioritize systemic therapies over local therapies in patients with HER2+ BCBM.

Introduction: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC., Methods: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m 2 IV weekly ×12 followed by doxorubicin 24 mg/m 2 IV weekly + cyclophosphamide 60 mg/m 2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade)., Results: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER + disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue., Conclusions: Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC., Competing Interests: Disclosure The following authors report they have conflicts of interest to disclose: JRG: Roche/Genentech (DSMC, Steering committee), Astra Zeneca (DSMC, consultant), Novartis (DSMC), Puma (advisory board), Immunomedics (DSMC), Radia (DSMC), Pfizer (advisory board), InBiomotion (advisory board), Sandoz/Hexal (Consultant), Genomic Health (advisory board) VG: SEngine Precision Medicine (ownership), AmunBio (Ownership), New Equilibrium Biosciences (Ownership), Seagen (Honoria/Consulting), Puma (Honoraria, Consulting), Sanofi (Honoraria/Consulting), Roche (research funding) BK: eResearch Technologies (Employer) AS: Amgen (grant funding/honoraria), AstraZeneca (consulting), Athenex (consulting) The remaining authors have no conflicts of interest to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Lessons Learned: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination., Background: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors., Methods: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab., Results: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation., Conclusion: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)

Purpose: This study evaluated the ability of 18 F-Fluorodeoxyglucose (FDG) and 18 F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors., Methods: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery., Results: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery., Conclusions: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response., (© 2021. The Author(s).)

Background Since 2007, digital mammography and digital breast tomosynthesis (DBT) replaced screen-film mammography. Whether these technologic advances have improved diagnostic performance has, to the knowledge of the authors, not yet been established. Purpose To evaluate the performance and outcomes of surveillance mammography (digital mammography and DBT) performed from 2007 to 2016 in women with a personal history of breast cancer and compare with data from 1996 to 2007 and the performance of digital mammography screening benchmarks. Materials and Methods In this observational cohort study, five Breast Cancer Surveillance Consortium registries provided prospectively collected mammography data linked with tumor registry and pathologic outcomes. This study identified asymptomatic women with American Joint Committee on Cancer anatomic stages 0-III primary breast cancer who underwent surveillance mammography from 2007 to 2016. The primary outcome was a second breast cancer diagnosis within 1 year of mammography. Performance measures included the recall rate, cancer detection rate, interval cancer rate, positive predictive value of biopsy recommendation, sensitivity, and specificity. Results Among 32 331 women who underwent 117 971 surveillance mammographic examinations (112 269 digital mammographic examinations and 5702 DBT examinations), the mean age at initial diagnosis was 59 years ± 12 (standard deviation). Of 1418 second breast cancers diagnosed, 998 were surveillance-detected cancers and 420 were interval cancers. The recall rate was 8.8% (10 365 of 117 971; 95% CI: 8.6%, 9.0%), the cancer detection rate was 8.5 per 1000 examinations (998 of 117 971; 95% CI: 8.0, 9.0), the interval cancer rate was 3.6 per 1000 examinations (420 of 117 971; 95% CI: 3.2, 3.9), the positive predictive value of biopsy recommendation was 31.0% (998 of 3220; 95% CI: 29.4%, 32.7%), the sensitivity was 70.4% (998 of 1418; 95% CI: 67.9%, 72.7%), and the specificity was 98.1% (114 331 of 116 553; 95% CI: 98.0%, 98.2%). Compared with previously published studies, interval cancer rate was comparable with rates from 1996 to 2007 in women with a personal history of breast cancer and was higher than the published digital mammography screening benchmarks. Conclusion In transitioning from screen-film to digital mammography and digital breast tomosynthesis, surveillance mammography performance demonstrated minimal improvement over time and remained inferior to the performance of screening mammography benchmarks. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Moy and Gao in this issue.

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the Kras LSL-G12D/+ ;p53 f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic., Competing Interests: Declaration of Interests S.S. and S.R.R. are inventors on a patent (“Immunogenic chemotherapy markedly enhances the efficacy of ROR1 CAR T cells in lung adenocarcinoma”; PCT/US2018/049812) filed by Fred Hutchinson Cancer Research Center and licensed by Lyell Immunopharma. S.S. holds equity and has served as a consultant for Lyell Immunopharma. D.G.M. has received research funding from Kite Pharma, Juno Therapeutics, and Celgene, and has served on advisory boards for Kite Pharma, Gilead, Genentech, Novartis, and Eureka Therapeutics. S.R.R. was a founder, has served as an advisor, and has patents licensed to Juno Therapeutics; is a founder of and holds equity in Lyell Immunopharma; and has served on the advisory boards for Adaptive Biotechnologies and Nohla. C.R. is named inventor on US Patent 9,758,586 claiming anti-ROR1 monoclonal antibodies R11 and R12 and is on the advisory board of NBE-Therapeutics. No potential conflicts of interest were disclosed by the other authors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. We tested whether 18 F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. 18 F-fluoroestradiol PET and 18 F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline 18 F-fluoroestradiol uptake was associated with longer progression-free survival. 18 F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18 F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher 18 F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18 F-fluoroestradiol PET., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The purpose of this study was to assess advanced imaging (bone scan, CT, or PET/CT) and serum tumor biomarker use in asymptomatic breast cancer survivors during the surveillance period., Patients and Methods: Cancer registry records for 2,923 women diagnosed with primary breast cancer in Washington State between January 1, 2007, and December 31, 2014, were linked with claims data from 2 regional commercial insurance plans. Clinical data including demographic and tumor characteristics were collected. Evaluation and management codes from claims data were used to determine advanced imaging and serum tumor biomarker testing during the peridiagnostic and surveillance phases of care. Multivariable logistic regression models were used to identify clinical factors and patterns of peridiagnostic imaging and biomarker testing associated with surveillance advanced imaging., Results: Of 2,923 eligible women, 16.5% (n=480) underwent surveillance advanced imaging and 31.8% (n=930) received surveillance serum tumor biomarker testing. Compared with women diagnosed before the launch of the Choosing Wisely campaign in 2012, later diagnosis was associated with lower use of surveillance advanced imaging (odds ratio [OR], 0.68; 95% CI, 0.52-0.89). Factors significantly associated with use of surveillance advanced imaging included increasing disease stage (stage III: OR, 3.65; 95% CI, 2.48-5.38), peridiagnostic advanced imaging use (OR, 1.76; 95% CI, 1.33-2.31), and peridiagnostic serum tumor biomarker testing (OR, 1.35; 95% CI, 1.01-1.80)., Conclusions: Although use of surveillance advanced imaging in asymptomatic breast cancer survivors has declined since the launch of the Choosing Wisely campaign, frequent use of surveillance serum tumor biomarker testing remains prevalent, representing a potential target for further efforts to reduce low-value practices.

Calibration and reproducibility of quantitative 18 F-FDG PET measures are essential for adopting integral 18 F-FDG PET/CT biomarkers and response measures in multicenter clinical trials. We implemented a multicenter qualification process using National Institute of Standards and Technology-traceable reference sources for scanners and dose calibrators, and similar patient and imaging protocols. We then assessed SUV in patient test-retest studies. Methods: Five 18 F-FDG PET/CT scanners from 4 institutions (2 in a National Cancer Institute-designated Comprehensive Cancer Center, 3 in a community-based network) were qualified for study use. Patients were scanned twice within 15 d, on the same scanner ( n = 10); different but same model scanners within an institution ( n = 2); or different model scanners at different institutions ( n = 11). SUV max was recorded for lesions, and SUV mean for normal liver uptake. Linear mixed models with random intercept were fitted to evaluate test-retest differences in multiple lesions per patient and to estimate the concordance correlation coefficient. Bland-Altman plots and repeatability coefficients were also produced. Results: In total, 162 lesions (82 bone, 80 soft tissue) were assessed in patients with breast cancer ( n = 17) or other cancers ( n = 6). Repeat scans within the same institution, using the same scanner or 2 scanners of the same model, had an average difference in SUV max of 8% (95% confidence interval, 6%-10%). For test-retest on different scanners at different sites, the average difference in lesion SUV max was 18% (95% confidence interval, 13%-24%). Normal liver uptake (SUV mean ) showed an average difference of 5% (95% confidence interval, 3%-10%) for the same scanner model or institution and 6% (95% confidence interval, 3%-11%) for different scanners from different institutions. Protocol adherence was good; the median difference in injection-to-acquisition time was 2 min (range, 0-11 min). Test-retest SUV max variability was not explained by available information on protocol deviations or patient or lesion characteristics. Conclusion: 18 F-FDG PET/CT scanner qualification and calibration can yield highly reproducible test-retest tumor SUV measurements. Our data support use of different qualified scanners of the same model for serial studies. Test-retest differences from different scanner models were greater; more resolution-dependent harmonization of scanner protocols and reconstruction algorithms may be capable of reducing these differences to values closer to same-scanner results., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Two data points from Table 1. (continued) were published in error. The corrected data in Table 1. (continued) are shown, in italic, below.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18 F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18 F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18 F-FDG PET and 18 F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18 F-FDG PET and 18 F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUV max ) and lean body mass adjusted standardized uptake (SUL peak ) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18 F-FDG PET and 18 F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18 F-FDG SUL peak at scan2 predicted shorter time to tSRE ( P = <0.001) and TTP ( P = 0.044). Higher 18 F-FDG SUV max at scan2 predicted a shorter time to tSRE ( P = <0.001). A multivariable model using 18 F-FDG SUV max of the index lesion at scan1 plus the difference in SUV max of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18 F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) ( P = 0.007, 0.028, respectively), with a trend toward improved survival ( P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18 F-NaF PET was associated with longer OS ( P = 0.027). Conclusion: Changes in 18 F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18 F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Doxorubicin in combination with cyclophosphamide is active in breast cancer; however, its use in metastatic cancer is limited owing to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was formulated to decrease the toxicity of conventional doxorubicin. We evaluated the safety and efficacy of PLD with metronomic oral cyclophosphamide., Patients and Methods: We conducted a single-arm open-label phase I/II study of PLD and oral cyclophosphamide in patients with metastatic breast cancer. In phase I, 3 escalating doses of PLD were planned (30, 35, and 40 mg/m 2 ) with cyclophosphamide (60 mg/m 2 orally daily) to determine the maximum tolerated dose (MTD). In phase II, the MTD of PLD in combination of oral cyclophosphamide was used to assess the primary endpoint of overall clinical response rate and secondary endpoints of progression-free survival, overall survival, and adverse events., Results: Thirty patients were enrolled in the study (n = 6 in phase I and n = 24 in phase II). The MTD of PLD from phase I was 30 mg/m 2 . The median progression-free and overall survival for the entire cohort were 6.4 months (95% confidence interval, 3.9 months to N/A) and 18.7 months (95% confidence interval, 15.1-31.5 months), respectively. A total of 21 (75%) patients had clinical benefit, including 6 (21%) patients with partial response and 15 (54%) patients with stable disease. The majority of toxicities were uncomplicated myelosuppression, and no infection or febrile neutropenia were noted in any patient., Conclusion: PLD in combination with daily oral cyclophosphamide is an active and tolerable regimen in metastatic breast cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine., Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response., Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1-6.7)., Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Clin Cancer Res; 22(12); 2855-64. ©2016 AACR., (©2016 American Association for Cancer Research.)

Unlabelled: Our objective was to determine whether early change in standardized uptake values (SUVs) of 3'deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) using PET with CT could predict pathologic complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NAC). The key secondary objective was to correlate SUV with the proliferation marker Ki-67 at baseline and after NAC., Methods: This prospective, multicenter phase II study did not specify the therapeutic regimen, thus, NAC varied among centers. All evaluable patients underwent (18)F-FLT PET/CT at baseline (FLT1) and after 1 cycle of NAC (FLT2); 43 patients were imaged at FLT1, FLT2, and after NAC completion (FLT3). The percentage change in maximum SUV (%ΔSUVmax) between FLT1 and FLT2 and FLT3 was calculated for the primary tumors. The predictive value of ΔSUVmax for pCR was determined using receiver-operating-characteristic curve analysis. The correlation between SUVmax and Ki-67 was also assessed., Results: Fifty-one of 90 recruited patients (median age, 54 y; stage IIA-IIIC) met the eligibility criteria for the primary objective analysis, with an additional 22 patients totaling 73 patients for secondary analyses. A pCR in the primary breast cancer was achieved in 9 of 51 patients. NAC resulted in a significant reduction in %SUVmax (mean Δ, 39%; 95% confidence interval, 31-46). There was a marginal difference in %ΔSUVmax&#95;FLT1-FLT2 between pCR and no-pCR patient groups (Wilcoxon 1-sided P = 0.050). The area under the curve for ΔSUVmax in the prediction of pCR was 0.68 (90% confidence interval, 0.50-0.83; Delong 1-sided P = 0.05), with slightly better predictive value for percentage mean SUV (P = 0.02) and similar prediction for peak SUV (P = 0.04). There was a weak correlation with pretherapy SUVmax and Ki-67 (r = 0.29, P = 0.04), but the correlation between SUVmax and Ki-67 after completion of NAC was stronger (r = 0.68, P < 0.0001)., Conclusion: (18)F-FLT PET imaging of breast cancer after 1 cycle of NAC weakly predicted pCR in the setting of variable NAC regimens. Posttherapy (18)F-FLT uptake correlated with Ki-67 on surgical specimens. These results suggest some efficacy of (18)F-FLT as an indicator of early therapeutic response of breast cancer to NAC and support future multicenter studies to test (18)F-FLT PET in a more uniformly treated patient population., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Commonly used adjuvant systemic therapies harbor high rates of severe short-term and long-term side effects but are often justified to patients because of curative intent in early-stage breast cancer. One of the oldest and least toxic adjuvant regimens, CMF (oral cyclophosphamide given with intravenous methotrexate and 5-fluorouracil), has been largely abandoned because of the perception that it underperforms for survival outcomes compared with modern regimens containing anthracycline and/or taxanes., Materials and Methods: To address this misperception, we performed a review of all consecutive breast cancer patients at the Seattle Cancer Care Alliance over the past decade who received 6 months of adjuvant CMF as their sole chemotherapy regimen and determined rates for relapse-free survival (RFS), overall survival (OS), and major organ toxicity. From January 2003 to August 2013, 248 patients (median age of 52 years at the start of chemotherapy) met criteria for inclusion in this series and had a median follow-up of 67 months., Results: RFS and OS at 5 years was 94.5% (91.3%-97.9%) and 98% (96%-100%), respectively. The only major organ toxicity that occurred in > 5% of patients was Grade 3 neutropenia (18.1%, 24 patients). One patient died during therapy from pneumocystis pneumonia attributed to previously undiagnosed AIDS., Conclusion: In a modern cohort of patients thoroughly characterized for Grade and hormone receptor status, CMF was a well-tolerated and effective adjuvant regimen for early-stage breast cancer and should be considered for appropriately selected patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial., Patients and Methods: Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression., Results: Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC., Conclusion: The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation., (© 2014 by American Society of Clinical Oncology.)

Purpose: 16α-[(18)F]-fluoro-17β-estradiol positron emission tomography (FES-PET) quantifies estrogen receptor (ER) expression in tumors and may provide diagnostic benefit., Procedures: Women with newly diagnosed metastatic breast cancer (MBC) from an ER-positive primary tumor were imaged before starting endocrine therapy. FES uptake was evaluated qualitatively and quantitatively, and associated with response and with ER expression., Results: Nineteen patients underwent FES imaging. Fifteen had a biopsy of a metastasis and 15 were evaluable for response. Five patients had quantitatively low FES uptake, six had at least one site of qualitatively FES-negative disease. All patients with an ER-negative biopsy had both low uptake and at least one site of FES-negative disease. Of response-evaluable patients, 2/2 with low FES standard uptake value tumors had progressive disease within 6 months, as did 2/3 with qualitatively FES-negative tumors., Conclusions: Low/absent FES uptake correlates with lack of ER expression. FES-positron emission tomography can help identify patients with endocrine resistant disease and safely measures ER in MBC.

Purpose: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis., Experimental Design: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m(2) twice daily (DL1 and DL2) or 1,000 mg/m(2) twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis., Results: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m(2) twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed., Conclusions: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m(2) twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect., (©2013 AACR.)

Background: In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or 'flare' response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response., Methods: Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis., Results: Forty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%., Conclusions: Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

Advances in our ability to assay molecular processes, including gene expression, protein expression, and molecular and cellular biochemistry, have fueled advances in our understanding of breast cancer biology and have led to the identification of new treatments for patients with breast cancer. The ability to measure biologic processes without perturbing them in vivo allows the opportunity to better characterize tumor biology and to assess how biologic and cytotoxic therapies alter critical pathways of tumor response and resistance. By accurately characterizing tumor properties and biologic processes, molecular imaging plays an increasing role in breast cancer science, clinical care in diagnosis and staging, assessment of therapeutic targets, and evaluation of responses to therapies. This review describes the current role and potential of molecular imaging modalities for detection and characterization of breast cancer and focuses primarily on radionuclide-based methods.