Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.

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.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer.

PURPOSE: To investigate combined MRI and 18F-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 18F-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 (K1) 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 18F-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 18F-FDG PET (K1) 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 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Variation in second breast cancer risk after primary invasive cancer by time since primary cancer diagnosis and estrogen receptor status.

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.

Accuracy of tumor registry versus pharmacy dispensings for breast cancer adjuvant endocrine therapy.

PURPOSE: Accounting for endocrine therapy use for breast cancer treatment is important for studies of survivorship. We evaluated the accuracy of Surveillance, Epidemiology, and End Results (SEER) breast cancer endocrine therapy data compared with pharmacy dispensings from an integrated health system. METHODS: We included women with non-metastatic hormone receptor positive primary breast cancer diagnosed between 1995 and 2017 enrolled in Kaiser Permanente Washington, linking their data with SEER. We used pharmacy dispensings for endocrine therapy within one year following diagnosis as our reference standard. We calculated kappa (concordance), positive predictive value (PPV), and negative predictive values (NPV) overall and stratified by woman and tumor characteristics of interest. RESULTS: Of 5,055 women, mean age at diagnosis was 62 years (interquartile range = 53-71); 53% had localized stage, 56% received lumpectomy with radiation, and 31% received chemotherapy. SEER data alone identified 67% of women as having received endocrine therapy; this increased to 75% with pharmacy dispensings. SEER's concordance with pharmacy dispensings was 0.68 (PPV = 91%; NPV = 76%). PPV did not vary by tumor or women characteristics; however, NPV declined with younger age at diagnosis (64% in < 45 years vs. 86% in 75+ years), increasing tumor stage (49% in regional stage vs. 91% in DCIS), and chemotherapy treatment (41% in those with chemotherapy vs. 83% in those without chemotherapy). CONCLUSION: Pharmacy dispensings enable more complete endocrine therapy capture, particularly in women with more advanced tumors or who receive chemotherapy. We determined woman, tumor, and treatment characteristics that contribute to underascertainment of endocrine therapy use in tumor registries.

18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-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.

First-In-Human, First-In-Class, Phase I Trial of the Fucosylation Inhibitor SGN-2FF in Patients with Advanced Solid Tumors.

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.

Single arm, phase two study of low-dose metronomic eribulin in metastatic breast cancer.

BACKGROUND: Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician's choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile. METHODS: We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy. FINDINGS: We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients. INTERPRETATION: Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

Digital Mammography and Breast Tomosynthesis Performance in Women with a Personal History of Breast Cancer, 2007-2016.

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.

Surveillance for second breast cancer events in women with a personal history of breast cancer using breast MRI: a systematic review and meta-analysis.

PURPOSE: Women with personal history of breast cancer (PHBC) are currently recommended to receive annual mammography for surveillance of breast cancer recurrence or new primary. However, given issues in accuracy with mammography, there is a need for evolving evidence-based surveillance recommendations with supplemental imaging. In this systematic review, we compiled and compared existing studies that describe the test performance of surveillance breast MRI among women with PHBC. METHODS: We searched PubMed and EMBASE using MeSH terms for studies (2000-2019) that described the diagnostic characteristics of breast MRI in women with PHBC. Search results were reviewed and included based on PICOTS criteria; quality of included articles was assessed using QUADAS-2. Meta-analysis of single proportions was conducted for diagnostic characteristics of breast MRI, including tests of heterogeneity. RESULTS: Our review included 11 articles in which unique cohorts were studied, comprised of a total of 8338 women with PHBC and 12,335 breast MRI done for the purpose of surveillance. We predict intervals (PI) for cancer detection rate per 1000 examinations (PI 9-15; I2 = 10%), recall rate (PI 5-31%; I2 = 97%), sensitivity (PI 58-95%; I2 = 47%), specificity (PI 76-97%; I2 = 97%), and PPV3 (PI 16-40%; I2 = 44%). CONCLUSIONS: Studies addressing performance of breast MRI are variable and limited in population-based studies. The summary of evidence to date is insufficient to recommend for or against use of breast MRI for surveillance among women with PHBC.

Patterns of Surveillance Advanced Imaging and Serum Tumor Biomarker Testing Following Launch of the Choosing Wisely Initiative.

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.

Adjuvant continuous metronomic adriamycin + cyclophosphamide followed by weekly nab-paclitaxel for high-risk early-stage breast cancer.

Many studies have sought to optimize the dosing schedule of adjuvant chemotherapy in early-stage breast cancer. Here, we assessed the use of continuous metronomic weekly doxorubicin plus daily oral cyclophosphamide (AC) with continuous G-CSF growth factor support for 12 weeks followed by weekly nab-paclitaxel (nP) for 12 weeks. A nonrandomized phase II clinical trial was designed to assess (1) DFS at 2 years, (2) dose delivered, (3) use of nP in the adjuvant setting, and (4) toxicities. The dosing of A was 24 mg/m2 IV weekly and C was 60 mg/m2 oral daily (with scheduled filgrastim 5mcg/kg 6 days/week); nP, 100 mg/m2 IV weekly. For patients with HER2 + disease, trastuzumab was started during the nP portion of therapy and continued for 12 months. Sixty patients enrolled with a median follow-up of 6 years. Node-positive disease was present in 58% of patients. Receptor categories included hormone receptor positive/HER2 negative (n = 25; 42%); triple negative (n = 19; 32%); or HER2 positive (n = 16; 27%). DFS at 2 years was 93%. Mean dose delivered was greater than 90% for metronomic AC and 88% for nP. Treatment was well tolerated with a 2% incidence of febrile neutropenia. Continuous metronomic AC followed by nP was well tolerated in our patients with comparable DFS to historical controls.

The Current and Future Roles of Precision Oncology in Advanced Breast Cancer.

Breast cancer is a common but heterogeneous disease characterized by several biologic features, including tumor grade, hormone receptor status, human epidermal growth factor receptor 2 status, and gene expression assays. These biologic and genomic features drive treatment decisions. In the advanced disease setting, inter- and intrapatient tumor heterogeneity is increasingly recognized as a challenge for optimizing treatment. Recent evidence and the recent approval of novel radiopharmaceuticals have increased recognition and acceptance of the potential of molecular imaging as a biomarker to impact and guide management decisions for advanced breast cancer.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

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 (18F-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 18F-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 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-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. 18F-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 18F-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 18F-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.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients with 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 (18F-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.In this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified as the maximum tumor voxel normalized by dose and body weight (SUVmax) and the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals of SUVmax and SULpeak were used to determine limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax in 38 bone tumors of the first cohort was 4.3%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and -16.3%, respectively. The 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification 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 changed the status of 3 patients compared to standard the standard Positron Emission Tomography Response Criteria in Solid Tumors of ±30% SULpeak. CONCLUSIONS: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG uptake, 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 18F-FDG imaging in clinical trials investigating bone lesions from these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

ACR Appropriateness Criteria® Imaging of Invasive Breast Cancer.

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.

qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.

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.

Secondary Breast Angiosarcoma After a Primary Diagnosis of Breast Cancer: A Retrospective Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database.

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.

Impact of Surveillance Mammography Intervals Less Than One Year on Performance Measures in Women With a Personal History of Breast Cancer.

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.

Correlation of SUV on Early Interim PET with Recurrence-Free Survival and Overall Survival in Primary Operable HER2-Positive Breast Cancer (the TBCRC026 Trial).

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SULmax) on 18F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18F-FDG PET/CT SULmax parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18F-FDG PET/CT (≥40% decline in SULmax between baseline and C1D15, or C1D15 SULmax ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SULmax of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SULmax decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SULmax of 3 or less on 18F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.