Sunitinib in Patients With Breast Cancer With FGFR1 or FGFR2 Amplifications or Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. METHODS: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. CONCLUSION: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

Nivolumab Plus Ipilimumab in Patients With Solid Tumors With ATM Mutations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = .84; α = .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% (P = .13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure. CONCLUSION: Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations.

Olaparib in Patients With Metastatic Prostate Cancer With BRCA1/2 Mutation: Results From the TAPUR Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to evaluate activity of approved targeted agents in patients with advanced cancers with potentially actionable genomic variants. Data from a cohort of patients with metastatic castrate-resistant prostate cancer (mCRPC) and BRCA1/2 mutations treated with olaparib are reported. METHODS: Eligible patients with measurable mCRPC were matched to treatment according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary end point of disease control, defined as objective response or stable disease of at least 16-week duration. Secondary end points include radiographic progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty patients with mCRPC with BRCA1/2 mutations were treated with olaparib. The disease control rate was 69% (95% CI, 51 to 81), and the objective response rate was 58% (95% CI, 37 to 77). The median radiographic progression-free survival and the median overall survival were 38.4 (95% CI, 16.3 to 52.1) weeks and 76.4 (95% CI, 49.3 to 106.0) weeks, respectively. Six of 30 (20%) patients experienced grade 3-4 adverse or serious adverse events including anemia, aspiration, decreased WBC count, and fatigue. CONCLUSION: Olaparib has antitumor activity in patients with mCRPC with BRCA1/2 mutations and warrants further study to determine how to best integrate it into the standard treatment of patients with BRCA1/2-mutated prostate cancer.

TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women over age 50 with BI-RADS 3, 4, or 5 Assessment.

PURPOSE: With improvements in breast cancer imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa Breast, in women over age 50 years. EXPERIMENTAL DESIGN: A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6-12 months and clinically relevant outcomes were recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. RESULTS: A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (breast cancer incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25-75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. CONCLUSIONS: Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.

A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women Under the Age of 50 Years.

BACKGROUND: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood-based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. PATIENTS AND METHODS: Provista-001 and Provista-002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor-associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista-001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista-002 cohort one (validation set). RESULTS: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow-up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow-up, a 67% reduction in FPs (P < .00001). CONCLUSIONS: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

Phase II trial of sequential therapy with fludarabine followed by cyclophosphamide, mitoxantrone, vincristine, and prednisone for low-grade follicular lymphomas.

Advanced follicular lymphomas, grades I and II, are indolent tumors but are not considered curable with standard therapy. Fludarabine has the highest single-agent response rates in this disease. However, fludarabine-based combination chemotherapy regimens have been associated with significant myelotoxicity. Data exist suggesting that the best way to combine partially non-cross-resistant agents may be to use them sequentially. Patients with bulky stage II, stage III, or stage IV follicular lymphoma (grade I or II) were entered on this protocol. Patients were treated with 3 cycles of fludarabine followed by 6-8 cycles of cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). Response was assessed after the 3(rd) cycle of fludarabine and after the 4(th), 6(th), and 8(th) cycles of CNOP. Twenty-seven patients were entered on the protocol. Median follow-up was 50 months. Eighteen patients (67%) attained a complete response (CR), and eight patients (30%) attained a partial response (PR), for an overall response rate of 97%. Median relapse-free survival was 34 months, and median overall survival was not reached for the entire cohort. While all patients who achieved only PR progressed, more than half of those in CR remain free of progression at 39-84 months of follow-up. The regimen was well tolerated. The sequential combination of fludarabine and CNOP appears to be active and well tolerated in patients with grade I and II follicular lymphoma. Patients who achieve CR fare best, and many remain disease-free long term. While these results are encouraging, the addition of other active agents such as rituximab to this regimen may further enhance efficacy and is under investigation.

Raloxifene is associated with less side effects than tamoxifen in women with early breast cancer: a questionnaire study from one physician's practice.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are being used increasingly for the prevention and treatment of breast cancer. The currently available SERMs, tamoxifen and raloxifene, are both associated with antiestrogenic side effects that can be bothersome. However, no data exist on how they compare in this regard. We conducted a retrospective, questionnaire-based study to answer this question. METHODS: Women with early breast cancer in one physician's practice who had received either or both of these drugs were surveyed using a self-administered questionnaire. Respondents graded the frequency and severity of side effects related to estrogen deprivation, such as vaginal dryness, mood changes, hot flashes, weight gain, and changes in libido, as well as other side effects, such as vaginal discharge. They were separated into three groups for analysis (group 1, tamoxifen only; group 2, raloxifene only; group 3, both drugs). Side effects graded 4 or 5 (or weight gain >10 pounds) were considered severe. RESULTS: Two hundred sixty-four questionnaires were available for analysis. Women on raloxifene had a shorter average duration of therapy. In comparing the tamoxifen and raloxifene groups, vaginal discharge, severe hot flashes, and weight gain of >10 pounds were significantly more frequent with tamoxifen. However, weight gain was also related to the duration of therapy with either drug. CONCLUSIONS: In this observational study, antiestrogenic side effects were common with either tamoxifen or raloxifene. Raloxifene is associated with significantly less vaginal discharge and severe hot flashes than tamoxifen in women with early breast cancer. Although weight gain of >10 pounds may also occur less frequently on this drug, this may be confounded by the shorter average duration of raloxifene therapy.