Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

Reliability of single-lead electrocardiogram interpretation to detect atrial fibrillation: insights from the SAFER Feasibility Study.

BACKGROUND AND AIMS: Single-lead electrocardiograms (ECGs) can be recorded using widely available devices such as smartwatches and handheld ECG recorders. Such devices have been approved for atrial fibrillation (AF) detection. However, little evidence exists on the reliability of single-lead ECG interpretation. We aimed to assess the level of agreement on detection of AF by independent cardiologists interpreting single lead ECGs, and to identify factors influencing agreement. METHODS: In a population-based AF screening study, adults aged ≥65 years old recorded four single-lead ECGs per day for 1-4 weeks using a handheld ECG recorder. ECGs showing signs of possible AF were identified by a nurse, aided by an automated algorithm. These were reviewed by two independent cardiologists who assigned participant- and ECG-level diagnoses. Inter-rater reliability of AF diagnosis was calculated using linear weighted Cohen's kappa (kw). RESULTS: Out of 2,141 participants and 162,515 ECGs, only 1,843 ECGs from 185 participants were reviewed by both cardiologists. Agreement was moderate: kw = 0.48 (95% CI, 0.37-0.58) at participant-level; and kw = 0.58 (0.53-0.62) at ECG-level. At participant-level, agreement was associated with the number of adequate-quality ECGs recorded, with higher agreement in participants who recorded at least 67 adequate-quality ECGs. At ECG-level, agreement was associated with ECG quality and whether ECGs exhibited algorithm-identified possible AF. CONCLUSION: Inter-rater reliability of AF diagnosis from single-lead ECGs was found to be moderate in older adults. Strategies to improve reliability might include participant and cardiologist training and designing AF detection programmes to obtain sufficient ECGs for reliable diagnoses.

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.

The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer.

PURPOSE: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. METHODS: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 -) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. RESULTS: Patients (N = 152) received GDC-0810 100-800 mg once daily (QD) or 300-400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). CONCLUSION: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .

Fluorine-18-Labeled Fluoroestradiol PET/CT: Current Status, Gaps in Knowledge, and Controversies-AJR Expert Panel Narrative Review.

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER+ breast cancer and received FDA approval in 2020 for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER+ breast cancer. Clinical use of FES PET/CT is increasing, but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the standalone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert workgroup in 2023; anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results; and the need for further research regarding use of FES PET/CT for ER-expressing nonbreast malignancies.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer.

BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).

Allogeneic hematopoietic cell transplantation in patients with a hematologic malignancy and a prior history of breast cancer.

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

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.

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.

Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance).

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT00684983.

Whole-Body Characterization of Estrogen Receptor Status in Metastatic Breast Cancer with 16α-18F-Fluoro-17ß-Estradiol Positron Emission Tomography: Meta-Analysis and Recommendations for Integration into Clinical Applications.

Estrogen receptor (ER) status by immunohistochemistry (IHC) of cancer tissue is currently used to direct endocrine therapy in breast cancer. Positron emission tomography (PET) with 16α-18F-fluoro-17ß-estradiol (18 F-FES) noninvasively characterizes ER ligand-binding function of breast cancer lesions. Concordance of imaging and tissue assays should be established for 18 F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. We conducted a meta-analysis of published results comparing 18 F-FES PET and tissue assays of ER status in patients with breast cancer. PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. Thresholds for imaging and tissue classification could differ between studies but had to be clearly stated. We used hierarchical summary receiver-operating characteristic curve models for the meta-analysis. The primary analysis included 113 nonbreast lesions from 4 studies; an expanded analysis included 327 total lesions from 11 studies. Treating IHC results as the reference standard, sensitivity was 0.78 (95% confidence region 0.65-0.88) and specificity 0.98 (0.65-1.00) for the primary analysis of nonbreast lesions. In the expanded analysis including non-IHC tissue assays and all lesion sites, sensitivity was 0.81 (0.73-0.87) and specificity 0.86 (0.68-0.94). These results suggest that 18 F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. We also review current best practices for conducting 18 F-FES PET scans. This imaging assay has potential to improve clinically relevant outcomes for patients with (historically) ER-positive metastatic breast cancer, including those with brain metastases and/or lobular histology. IMPLICATIONS FOR PRACTICE: 16α-18F-fluoro-17ß-estradiol positron emission tomography (18 F-FES PET) imaging assesses estrogen receptor status in breast cancer in vivo. This work reviews the sensitivity and specificity of 18 F-FES PET in a meta-analysis with reference tissue assays and discusses best practices for use of the tracer as an imaging biomarker. 18 F-FES PET could enhance breast cancer diagnosis and staging as well as aid in therapy selection for patients with metastatic disease. Tissue sampling limitations, intrapatient heterogeneity, and temporal changes in molecular markers make it likely that 18 F-FES PET will complement existing assays when clinically available in the near future.

A Pilot Study of a Comprehensive Financial Navigation Program in Patients With Cancer and Caregivers.

BACKGROUND: Few studies have engaged patients and caregivers in interventions to alleviate financial hardship. We collaborated with Consumer Education and Training Services (CENTS), Patient Advocate Foundation (PAF), and Family Reach (FR) to assess the feasibility of enrolling patient-caregiver dyads in a program that provides financial counseling, insurance navigation, and assistance with medical and cost of living expenses. METHODS: Patients with solid tumors aged ≥18 years and their primary caregiver received a financial education video, monthly contact with a CENTS counselor and PAF case manager for 6 months, and referral to FR for help with unpaid cost of living bills (eg, transportation or housing). Patient financial hardship and caregiver burden were measured using the Comprehensive Score for Financial Toxicity-Patient-Reported Outcomes (COST-PRO) and Caregiver Strain Index (CSI) measures, respectively, at baseline and follow-up. RESULTS: Thirty patients (median age, 59.5 years; 40% commercially insured) and 18 caregivers (67% spouses) consented (78% dyad participation rate). Many participants faced cancer-related financial hardships prior to enrollment, such as work change or loss (45% of patients; 39% of caregivers) and debt (64% of patients); 39% of caregivers reported high levels of financial burden at enrollment. Subjects received $11,000 in assistance (mean, $772 per household); 66% of subjects with income ≤$50,000 received cost-of-living assistance. COST-PRO and CSI scores did not change significantly. CONCLUSIONS: Patient-caregiver dyads were willing to participate in a financial navigation program that addresses various financial issues, particularly cost of living expenses in lower income participants. Future work should address financial concerns at diagnosis and determine whether doing so improves patient and caregiver outcomes.

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.

Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression.

Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using (18)F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.

Satisfaction with cancer care among American Indian and Alaska Natives in Oregon and Washington State: a qualitative study of survivor and caregiver perspectives.

PURPOSE: To better understand satisfaction with care among American Indian and Alaska Native (AI/AN) persons with cancer, we explored dimensions of the provider relationship that contributed to satisfaction among caregivers and survivors who received cancer treatment in Oregon and Washington State. METHODS: Between November 2011 and April 2013, the project team interviewed 11 caregivers and 71 AI/AN cancer survivors residing in Oregon and Washington State. Interview questions aimed to elicit participant experiences with care providers and factors associated with cancer care satisfaction. Interviews were analyzed using an inductive content analysis approach in which concepts were identified and themes derived from interview data. RESULTS: Three overarching themes, each with two sub-themes, emerged from the data: (1) universal factors: bolstering understanding, involvement, and empathy in care; (2) minority-specific factors: incorporating culture and community into care; and (3) AI/AN-unique factors: interacting with Indian health clinics and Indian Health Service (IHS). CONCLUSIONS: The results of our study suggest that satisfaction with care among survivors and their caregivers must be examined within the context of culture and community, particularly among minority patients. Our study demonstrates providers' critical role in ensuring AI/AN patients emerge satisfied with cancer treatment by honoring their AI/AN-specific needs, such as respect for integration of traditional healing modalities and navigation of specialty care coordination.

The use of stereotactic radiosurgery for brain metastases from breast cancer: who benefits most?

Brain metastases (BM) from primary breast cancer can arise despite use of systemic therapies that provide excellent extracranial disease control. Local modalities for treating BM include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). We sought to determine the benefits of SRS for management of BM arising from different biologic breast cancer subtypes. We reviewed records of 131 patients who received SRS for breast cancer BM between 2001 and 2013. Survival was estimated by the Kaplan-Meier method. Effects of tumor biology, number and location of lesions, and number of SRS sessions on survival were evaluated by Cox proportional hazards regression. Of the 122 patients with subtypes available, 41 patients (31%) were classified as estrogen receptor positive/HER2 negative (ER(+)HER2(-)); 30 patients (23%), ER(+)HER2(+); 23 patients (18%), ER(-)HER2(+); and 28 patients (21%), ER(-)HER2(-) (or triple negative breast cancer, TNBC). Median age at first SRS was 50 years. Median overall survival for ER(+)HER2(-), ER(+)HER2(+), ER(-)HER2(+), and TNBC was 16, 26, 23, and 7 months, respectively (p < 0.001 for difference between groups). Patients with TNBC had the shortest time to retreatment with WBRT or SRS or death with hazard ratio of 3.12 (p < 0.001) compared to ER(+)HER2(-). In all subtypes other than TNBC, SRS can provide meaningful control of BM even in the setting of multiple lesions and may be worth repeating for new lesions that develop metachronously. For patients with TNBC, prognosis is guarded following SRS, and there is an urgent need to develop more effective treatment strategies.

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.

BACKGROUND: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. METHODS: In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. FINDINGS: Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. INTERPRETATION: Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. FUNDING: Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.

Trends in 5-year survival rates among breast cancer patients by hormone receptor status and stage.

Improvement in breast cancer survival has been observed in recent decades in the U.S., but it is unclear if similar survival gains are consistent across breast cancer subtypes, especially with regards to more advanced stages of the disease. Data were from 13 population-based cancer registries participating in the surveillance, epidemiology, and end results (SEER) program, consisting of women between 20 and 79 years of age diagnosed with invasive breast cancer between 1992 and 2008. 2-year (1992-2008) and 5-year (1992-2006) breast cancer cause-specific survival rates were calculated and stratified by estrogen receptor (ER)/progesterone receptor (PR) status, stage, and race. Annual percent changes in survival rates were assessed. From 1992 through 1998-1999, 5- and 2-year cause-specific survival rates significantly improved across ER+/PR+, ER-/PR-, and ER+/PR- subtypes, with an annual increase ranging from 0.5 to 1.0 % in the 5-year rates. From 1998-1999 to 2006, different patterns were observed by ER/PR subtypes with survival rates slightly improving for ER+/PR+, continuing to improve at a rate of 0.5 % per year for ER-/PR-, and dropping 0.3 % annually for ER+/PR-. No significant survival gains were experienced by patients with ER-/PR+ cancer during the study period. In terms of advanced diseases, greatest annual increases in survival rates were seen for patients with stage III-IV ER+/PR+ and ER-/PR- tumors but less progress was observed for advanced ER+/PR- breast cancers. Steady improvements in survival rates for breast cancer have been achieved over the past several decades. However, 5-year survival rates for stage IV disease remained dismally below 20 % for most ER/PR subtypes.

Summary: SNMMI Procedure Standard/EANM Practice Guideline for Estrogen Receptor Imaging of Patients with Breast Cancer Using 16α-[18F]Fluoro-17ß-Estradiol PET.

The estrogen receptor (ER), a steroid hormone receptor important in female physiology, is a significant contributor to breast carcinogenesis and progression and, as such, is an important therapeutic target. Approximately 70% of breast cancers will express ER at presentation, and the determination of ER expression by tissue assay, usually by immunohistochemistry, is part of the standard of care for newly diagnosed breast cancer. ER expression is important in guiding the approach to treatment, especially with the increase in relevant systemic therapies. The ER-targeting imaging agent 16α-[18F]fluoro-17ß-estradiol ([18F]FES) is approved for clinical use by regulatory agencies in France and the United States. Multiple studies suggest the advantages of [18F]FES PET in assessing tumor ER expression, the ability of both qualitative and quantitative [18F]FES PET measures to predict response to ER-targeted therapy, and the ability of [18F]FES PET to clarify equivocal staging and restaging results in patients with ER-expressing cancers. [18F]FES PET/CT may also be helpful in staging invasive lobular breast cancer and low-grade ER-expressing invasive ductal cancers and, in some cases, may be a substitute for biopsy. The Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine in June 2023 released a procedure standard/practice guideline for [18F]FES PET ER imaging of patients with breast cancer. The goal of the standard/guideline is to assist physicians in recommending, performing, interpreting, and reporting the results of [18F]FES PET studies for patients with breast cancer and to provide clinicians with the best available evidence, inform them about areas where robust evidence is lacking, and help them deliver the best possible diagnostic efficacy and study quality for their patients. Also reviewed are standardized quality control, quality assurance, and imaging procedures for [18F]FES PET. The authors emphasize the importance of precision, accuracy, repeatability, and reproducibility for both clinical management of patients and for use of [18F]FES PET in multicenter trials. A standardized imaging procedure, in combination with already published appropriate-use criteria, will help promote the use of [18F]FES PET and enhance subsequent research. This brief summary article reviews the content of the joint standard/guideline, which is available in its entirety at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=6414&navItemNumbe=10790.

Alcohol, Smoking, and Risks of Breast Cancer Recurrence and Mortality among Women with Luminal, Triple-Negative, and HER2-Overexpressing Breast Cancer.

BACKGROUND: This study evaluates the relationship between smoking, alcohol, and breast cancer outcomes according to molecular subtype. METHODS: This population-based prospective cohort consisted of 3,876 women ages 20 to 69 diagnosed with a first primary invasive breast cancer from 2004 to 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 expressions: luminal (ER+), triple-negative (TN; ER-/PR-/HER2-), and HER2-overexpressing (H2E; ER-/HER2+). We fit Cox proportional hazards models to assess the association between alcohol consumption and smoking status at diagnosis and risks of recurrence, breast cancer-specific mortality, and all-cause mortality. RESULTS: Histories of ever smoking [HR, 1.33; 95% confidence interval (CI), 1.01-1.74] and current smoking (HR, 1.59; 95% CI, 1.07-2.35) were associated with greater risk of breast cancer recurrence among TN cases. Smoking was also associated with greater risk of recurrence to bone among all cases and among luminal cases. Elevated risks of breast cancer-specific and all-cause mortality were observed among current smokers across all subtypes. Alcohol use was not positively associated with risk of recurrence or mortality overall; however, TN patients who drank four or more drinks per week had a decreased risk of recurrence (HR, 0.71; 95% CI, 0.51-0.98) and breast cancer-specific mortality (HR, 0.73; 95% CI, 0.55-0.97) compared with non-current drinkers. CONCLUSIONS: Patients with breast cancer with a history of smoking at diagnosis have elevated risks of recurrence and mortality. IMPACT: These findings underscore the need to prioritize smoking cessation among women diagnosed with breast cancer.