Utility of Stereotactic Body Radiation Therapy in Establishing Local Control for Patients With Invasive Breast Cancer Not Undergoing Definitive Surgery.

PURPOSE: Surgery is the backbone of breast cancer (BC) treatment. For patients who cannot undergo surgery, improving local control (LC) of the primary tumor is paramount. To that end, this study explored the role of stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Between 2015 and 2022, 21 nonsurgical candidates (10 metastatic, 11 stage IA-IIIC) received 23 SBRT courses to primary BC. Seven were analyzed retrospectively; 15 are currently enrolled in a prospective study. SBRT (40 Gy/5 fractions) was delivered every other day. Follow-up imaging was reviewed. Acute (≤3 months) and late toxicities were evaluated using Common Terminology Criteria for Adverse Events, version 5. LC and overall survival (OS) were estimated using Kaplan-Meier curves. RESULTS: Median age was 78.4 years (45.9-97.3). Median follow-up was 14.7 months (3.3-70.3). Median pre-SBRT index lesion size was 3.1 cm (0.5-14.5) and planning treatment volume was 32.4 cc (11.5-522.4). Initial posttreatment imaging performed at a median 4.0 months (0.6-11.9) post-SBRT demonstrated median decrease in index lesion size of 20.8% (0%-100%); SUV reduction of 65.2% (20.8%-100%). Second follow-up scans at a median 7.8 months post-SBRT showed 62% (0%-100%) and 88% (33.3%-100%) median reduction in tumor size and SUV, respectively, compared with pre-SBRT values. The estimated LC rate was 100% at 6 months and 93.3% at 12, 24, and 36 months. Local progression occurred in 1 case 9.5 months after SBRT, after an initial response. Regional progression occurred in 4 cases (17.4%) at a median 18.6 months (5.2-22.7) post-SBRT. Six patients (35.3%) developed distant progression at a median 2.7 months (0.9-16.2). The estimated OS was 85.7% at 6 months, 69.6% at 12 months, and 63.8% at 24 and 36 months. The rates of acute toxicity were G1: 47.8%, G2: 4.3%, G3: 8.7%, and G4: 0%. CONCLUSIONS: Definitive SBRT for primary BC resulted in good LC in nonsurgical patients and was well-tolerated. Considering the pattern of progression, additional approaches to improve regional/distant control should be investigated.

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

PURPOSE: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC). PATIENTS AND METHODS: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS). RESULTS: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year. CONCLUSIONS: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.

Two fully automated data-driven 3D whole-breast segmentation strategies in MRI for MR-based breast density using image registration and U-Net with a focus on reproducibility.

Presence of higher breast density (BD) and persistence over time are risk factors for breast cancer. A quantitatively accurate and highly reproducible BD measure that relies on precise and reproducible whole-breast segmentation is desirable. In this study, we aimed to develop a highly reproducible and accurate whole-breast segmentation algorithm for the generation of reproducible BD measures. Three datasets of volunteers from two clinical trials were included. Breast MR images were acquired on 3 T Siemens Biograph mMR, Prisma, and Skyra using 3D Cartesian six-echo GRE sequences with a fat-water separation technique. Two whole-breast segmentation strategies, utilizing image registration and 3D U-Net, were developed. Manual segmentation was performed. A task-based analysis was performed: a previously developed MR-based BD measure, MagDensity, was calculated and assessed using automated and manual segmentation. The mean squared error (MSE) and intraclass correlation coefficient (ICC) between MagDensity were evaluated using the manual segmentation as a reference. The test-retest reproducibility of MagDensity derived from different breast segmentation methods was assessed using the difference between the test and retest measures (Δ2-1), MSE, and ICC. The results showed that MagDensity derived by the registration and deep learning segmentation methods exhibited high concordance with manual segmentation, with ICCs of 0.986 (95%CI: 0.974-0.993) and 0.983 (95%CI: 0.961-0.992), respectively. For test-retest analysis, MagDensity derived using the registration algorithm achieved the smallest MSE of 0.370 and highest ICC of 0.993 (95%CI: 0.982-0.997) when compared to other segmentation methods. In conclusion, the proposed registration and deep learning whole-breast segmentation methods are accurate and reliable for estimating BD. Both methods outperformed a previously developed algorithm and manual segmentation in the test-retest assessment, with the registration exhibiting superior performance for highly reproducible BD measurements.

Blood plasma derived extracellular vesicles (BEVs): particle purification liquid chromatography (PPLC) and proteomic analysis reveals BEVs as a potential minimally invasive tool for predicting response to breast cancer treatment.

PURPOSE: Circulating blood plasma derived extracellular vesicles (BEVs) containing proteins hold promise for their use as minimally invasive biomarkers for predicting response to cancer therapy. The main goal of this study was to establish the efficiency and utility of the particle purification liquid chromatography (PPLC) BEV isolation method and evaluate the role of BEVs in predicting breast cancer (BC) patient response to neoadjuvant chemotherapy (NAC). METHODS: PPLC isolation was used to separate BEVs from non-EV contaminants and characterize BEVs from 17 BC patients scheduled to receive NAC. Using LC-MS/MS, we compared the proteome of PPLC-isolated BEVs from patients (n = 7) that achieved a pathological complete response (pCR) after NAC (responders [R]) to patients (n = 10) who did not achieve pCR (non-responders [NR]). Luminal MCF7 and basaloid MDA-MB-231 BC cells were treated with isolated BEVs and evaluated for metabolic activity by MTT assay. RESULTS: NR had elevated BEV concentrations and negative zeta potential (ζ-potential) prior to receipt of NAC. Eight proteins were enriched in BEVs of NR. GP1BA (CD42b), PECAM-1 (CD31), CAPN1, HSPB1 (HSP27), and ANXA5 were validated using western blot. MTT assay revealed BEVs from R and NR patients increased metabolic activity of MCF7 and MDA-MB-231 BC cells and the magnitude was highest in MCF7s treated with NR BEVs. CONCLUSION: PPLC-based EV isolation provides a preanalytical separation process for BEVs devoid of most contaminants. Our findings suggest that PPLC-isolated BEVs and the five associated proteins may be established as predictors of chemoresistance, and thus serve to identify NR to spare them the toxic effects of NAC.

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach.

Background: Clinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. Purpose: We aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. Conclusion: This analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.

Experience with denosumab (XGEVA®) for prevention of skeletal-related events in the 10 years after approval.

Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor approved for SRE prevention in patients with multiple myeloma and patients with bone metastases from solid tumors. In phase 3 trials, denosumab showed superiority to the bisphosphonate zoledronate in reducing the risk of first on-study SRE by 17% (median time to first on-study SRE delayed by 8.2 months) and the risk of first and subsequent on-study SREs by 18% across multiple solid tumor types, including some patients with multiple myeloma. Denosumab also improved pain outcomes and reduced the need for strong opioids. Additionally, a phase 3 trial showed denosumab was noninferior to zoledronate in delaying time to first SRE in patients with newly diagnosed multiple myeloma. Denosumab has a convenient 120 mg every 4 weeks recommended dosing schedule with subcutaneous administration. Rare but serious toxicities associated with denosumab include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture events, with multiple vertebral fractures reported following treatment discontinuation. After a decade of real-world clinical experience with denosumab, we are still learning about the optimal use and dosing for denosumab. Despite the emergence of novel and effective antitumor therapies, there remains a strong rationale for the clinical utility of antiresorptive therapy for SRE prevention. Ongoing studies aim to optimize clinical management of patients using denosumab for SRE prevention while maintaining safety and efficacy.

Sulindac Improves Stiffness and Quality of Life in Women Taking Aromatase Inhibitors for Breast Cancer.

PURPOSE: To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). METHODS: Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. RESULTS: Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity. CONCLUSIONS: Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT01761877, December, 2012.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer.

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/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 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.

Case report: Metastatic metaplastic breast cancer with choriocarinomatous features: Targeting the choriocarcinoma component for cure.

Breast cancer with choriocarcinomatous features (BCCF) is a rare and aggressive breast cancer. BCCF carries a poor prognosis and there is unfortunately scant literature to guide treatment beyond surgical resection with most patients receiving standard regimens for breast cancer. In our case, we present a 42-year-old female with an initial hCG of 2,324 and two suspicious lesions of the right breast. On biopsy, each lesion had distinct histopathology with the larger lesion diagnosed as BCCF and the smaller lesion being an invasive ER/PR positive ductal carcinoma. The diagnosis of BCCF rather than metastatic choriocarcinoma was confirmed using DNA typing. Salvage chemotherapy targeting choriocarcinoma resulted in marked clinical and biomarker success including normalization of the hCG. After recurrent brain metastases were diagnosed, high dose chemotherapy with methotrexate was administered resulting in long term remission.

Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors.

PURPOSE: To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. EXPERIMENTAL DESIGN: An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor-positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. RESULTS: In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), -14.6 to -4.7] at 12 months, an absolute decrease of -1.4% (95% CI, -2.5 to -0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). CONCLUSIONS: This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.

Changes in serum estradiol levels with Estring in postmenopausal women with breast cancer treated with aromatase inhibitors.

BACKGROUND: Anti-estrogen therapy is an effective intervention for preventing reoccurrence of hormone receptor-positive breast cancer in women. However, the side effects of anti-estrogen therapy, including urogenital symptoms, have been reported to cause significant morbidity. There is controversial data, mainly due to small sample sizes, reporting on the safety and efficacy of using vaginal estrogen to treat urogenital symptoms in patients on aromatase inhibitor therapy. METHODS: We proposed a prospective trial to measure the change in blood estradiol levels in postmenopausal women with hormone receptor-positive breast cancer undergoing treatment with aromatase inhibitors when treated with vaginal estrogen preparation, Estring, for their urogenital symptoms. Only 8 prospective patients were enrolled, and the study was amended to include 6 retrospective patients who were treated similarly. Blood estradiol levels were measured at baseline and at week 16 for all patients. RESULTS: The median age for all patients was 55 years, and the majority of them were treated with anastrozole. There was no significant difference between baseline and week 16 estradiol levels (p = 0.81). In addition, patients in the prospective group reported subjective improvement in their vaginal dryness symptoms questionnaires. CONCLUSIONS: The vaginal estrogen preparation, Estring, did not cause persistent elevations in serum estradiol levels and might be a safer option for women with significant urogenital symptoms requiring estrogen therapy. IMPLICATIONS FOR CANCER SURVIVORS: Vaginal estrogen preparation, Estring, might be an option for women with hormone receptor positive breast cancer who have persistent urogenital symptoms.

Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States.

Aims: Bone complications (also known as skeletal-related events [SREs]) pose significant health and financial burdens on patients with bone metastases. Denosumab demonstrated superiority over zoledronic acid in delaying the time to first SRE. This study examined the lifetime cost-effectiveness of denosumab vs zoledronic acid from both US payer and societal perspectives.Methods: This analysis used a lifetime Markov model and included patients with breast cancer, prostate cancer, and other solid tumors and bone metastases. The societal perspective included direct medical, direct non-medical, and indirect costs associated with denosumab and zoledronic acid; the payer perspective included direct medical costs only. Bone complication rates for each tumor type were estimated from three pivotal phase 3 studies and modified to reflect real-world incidence.Results: From a societal perspective, compared with zoledronic acid, denosumab use resulted in an incremental cost of $9,043, an incremental benefit of 0.128 quality-adjusted life-years (QALYs), a lifetime cost per QALY of $70,730, and a net monetary benefit (NMB) of $10,135 in favor of denosumab. Direct drug costs for denosumab ($28,352) were higher than zoledronic acid/untreated ($578), but were offset by reduced costs associated with bone complications. From a payer perspective, denosumab use was associated with an incremental cost of $13,396, and an incremental benefit of 0.128 QALYs, for a cost of $104,778 per QALY and an NMB of $5,782 in favor of denosumab.Limitations: Some model inputs had limited information and, given that the results may be sensitive to changes in these inputs, our findings should be interpreted within the context of the data inputs and modeling assumptions used in the analysis.Conclusions: Denosumab is a cost-effective option to prevent bone complications in patients with solid tumors when considering both payer and broader societal perspectives.

Phase III Randomized Trial of Bisphosphonates as Adjuvant Therapy in Breast Cancer: S0307.

BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

A Phase II Study of Irinotecan and Etoposide as Treatment for Refractory Metastatic Breast Cancer.

LESSONS LEARNED: The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events. BACKGROUND: As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC). METHODS: This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen. RESULTS: We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy. CONCLUSION: Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.

Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer.

INTRODUCTION: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2-positive breast cancer in an open-label phase 1b clinical study. PATIENTS AND METHODS: Women with human epidermal growth factor receptor 2-positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). RESULTS: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration-time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. CONCLUSION: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response.

Reproducible automated breast density measure with no ionizing radiation using fat-water decomposition MRI.

BACKGROUND: Increased breast density is a significant independent risk factor for breast cancer, and recent studies show that this risk is modifiable. Hence, breast density measures sensitive to small changes are desired. PURPOSE: Utilizing fat-water decomposition MRI, we propose an automated, reproducible breast density measurement, which is nonionizing and directly comparable to mammographic density (MD). STUDY TYPE: Retrospective study. POPULATION: The study included two sample sets of breast cancer patients enrolled in a clinical trial, for concordance analysis with MD (40 patients) and reproducibility analysis (10 patients). FIELD STRENGTH/SEQUENCE: The majority of MRI scans (59 scans) were performed with a 1.5T GE Signa scanner using radial IDEAL-GRASE sequence, while the remaining (seven scans) were performed with a 3T Siemens Skyra using 3D Cartesian 6-echo GRE sequence with a similar fat-water separation technique. ASSESSMENT: After automated breast segmentation, breast density was calculated using FraGW, a new measure developed to reliably reflect the amount of fibroglandular tissue and total water content in the entire breast. Based on its concordance with MD, FraGW was calibrated to MR-based breast density (MRD) to be comparable to MD. A previous breast density measurement, Fra80-the ratio of breast voxels with <80% fat fraction-was also calculated for comparison with FraGW. STATISTICAL TESTS: Pearson correlation was performed between MD (reference standard) and FraGW (and Fra80). Test-retest reproducibility of MRD was evaluated using the difference between test-retest measures (Δ1-2 ) and intraclass correlation coefficient (ICC). RESULTS: Both FraGW and Fra80 were strongly correlated with MD (Pearson ρ: 0.96 vs. 0.90, both P < 0.0001). MRD converted from FraGW showed higher test-retest reproducibility (Δ1-2 variation: 1.1% ± 1.2%; ICC: 0.99) compared to MD itself (literature intrareader ICC ≤0.96) and Fra80. DATA CONCLUSION: The proposed MRD is directly comparable with MD and highly reproducible, which enables the early detection of small breast density changes and treatment response. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:971-981.

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen.

PURPOSE: Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen. METHODS: Women prescribed tamoxifen (n = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. RESULTS: Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (-0.7 [-1.7, 0.8], P < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 ± 22 and +1.1 ± 19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo (P < 0.001). Minimal adverse events were reported and did not differ by treatment arm. CONCLUSION: In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR-DIM associated decreases in tamoxifen metabolites, including effects on endoxifen levels, attenuates the clinical benefit of tamoxifen. TRIAL REGISTRATION: ClinicalTrials.gov NCT01391689.

Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.

BACKGROUND: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. METHODS/DESIGN: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. DISCUSSION: The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.