Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer.

BACKGROUND: Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response. METHODS: Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2. RESULTS: 32 patients enrolled from 11/2012-5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress ßII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with ßII and BAX overexpression, OS was significantly shorter in those with ßIII and BAX overexpression. These associations remained after multivariate analysis. CONCLUSIONS: Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. ßII, ßIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.

Effect of Chemotherapy on the Gut Microbiome of Breast Cancer Patients During the First Year of Treatment.

Introduction: There is accumulating information of the effects of chemotherapy and weight changes on the gut microbiome of breast cancer patients. Methods: In this 1-year follow-up study, we investigated gut microbiome of 33 breast cancer patients who donated fecal samples at baseline and after completion of treatment. We compared alpha diversity and mean taxa abundance at baseline and absolute taxa abundance changes (final-baseline) by treatment (16 neoadjuvant [neoADJ], 13 adjuvant [ADJ], 4 no chemotherapy [noC]) and specific chemotherapy agent using Wilcoxon rank sum and negative binomial mixed model (NBMM) analysis. Results: All four gut alpha diversity measures changed in association with chemotherapy treatment; they increased in the neoADJ (+16.4% OTU p = 0.03; +51.6% Chao1 p = 0.03; +7.0% Shannon index p = 0.02; +11.0% PD whole tree p = 0.09) but not in the ADJ and noC group (ADJ+noC). The difference in Chao1 index change between groups was statistically significant (pneoADJ vs. ADJ+noC=0.04). Wilcoxon p values of 0.03-0.003 were observed for five taxa. In NBMM analysis, changes in taxa abundance differed (Bonferroni-adjusted p ≤ 0.0007) for two Bacteroidetes taxa (g_Alistipes, f_S24-7) and two Firmicutes taxa (g_Catenibacterium, g_Eubacterium). NBMM analysis results remained unchanged with adjustment for weight changes. Alpha diversity changes were also found by receipt of chemotherapy agents. Consistent increases in alpha diversity were observed among those treated with TCHP (OTU p = 0.009; Chao1 p = 0.02; Shannon p = 0.02; PD whole tree p = 0.05) but not AC, Taxol or Herceptin. Those treated with TCHP or Herceptin showed increases in Verrucomicrobia (g_Akkermansia) but decreases of Bacteroidetes(g_Alistipes); the differences in changes in taxa abundance were statistically significant. Conclusion: Results from this pilot longitudinal study support an effect of chemotherapy, particularly neoADJ on the gut microbiome of breast cancer patients even after adjustment for weight changes. Further investigations are needed to confirm these findings in larger studies and with longer follow-up and to assess the impact of these microbiome changes on patient outcome.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I.

PURPOSE: PIK3CA mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in PIK3CA-mutant breast cancer. Whether PIK3CA mutations predict sensitivity to taselisib in other cancer types is unknown. National Cancer Institute-Molecular Analysis for Therapy Choice Arm EAY131-I is a single-arm, phase II study of the safety and efficacy of taselisib in patients with advanced cancers. METHODS: Eligible patients had tumors with an activating PIK3CA mutation. Patients with breast or squamous cell lung carcinoma, or whose cancer had KRAS or PTEN mutations, were excluded. Patients received taselisib 4 mg, orally once daily continuously, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival (OS), and identification of predictive biomarkers. RESULTS: Seventy patients were enrolled, and 61 were eligible and initiated protocol therapy. Types of PIK3CA mutations included helical 41 of 61 (67%), kinase 11 of 61 (18%), and other 9 of 61 (15%). With a median follow-up of 35.7 months, there were no complete or partial responses. Six-month PFS was 19.9% (90% CI, 12.0 to 29.3) and median PFS was 3.1 months (90% CI, 1.8 to 3.7). Six-month OS was 60.7% (90% CI, 49.6 to 70.0) and median OS was 7.2 months (90% CI, 5.9 to 10.0). Individual comutations were too heterogeneous to correlate with clinical outcome. Fatigue, diarrhea, nausea, and hyperglycemia were the most common toxicities, and most were grade 1 and 2. CONCLUSION: In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA-mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity.

Bariatric surgery in patients with breast and endometrial cancer in California: population-based prevalence and survival.

BACKGROUND: The number of bariatric surgeries performed in the United States has increased substantially since the 1990's. However, the prevalence and prognostic impact of bariatric surgery, or weight loss surgery (WLS), among patients with cancer are not known. OBJECTIVES: We investigated the population-based prevalence of WLS in women with breast or endometrial cancer and conducted exploratory analysis to examine whether postdiagnosis WLS is associated with survival. SETTING: Administrative statewide database. METHODS: WLS records for women with nonmetastasized breast (n = 395,146) or endometrial (n = 69,859) cancer were identified from the 1991-2014 California Cancer Registry data linked with the California Office of Statewide Health Planning and Development database. Characteristics of the patients were examined according to history of WLS. Using body mass index data available since 2011, a retrospective cohort of patients with breast or endometrial cancer and obesity (n = 12,540) was established and followed until 2017 (5% lost to follow-up). Multivariable cause-specific Cox proportional hazards models were used to examine the associations between postdiagnostic WLS and time to death. RESULTS: WLS records were identified for 2844 (.7%) patients with breast cancer and 1140 (1.6%) patients with endometrial cancer; about half of the surgeries were performed after cancer diagnosis. Postdiagnosis WLS was performed in ∼1% of patients with obesity and was associated with a decreased hazard for death (cause-specific hazard ratio = .37; 95% confidence interval = .014-.99; P = .049), adjusting for age, stage, co-morbidity, race/ethnicity, and socioeconomic status. CONCLUSION: About 2000 patients with breast or endometrial cancer in California underwent post-diagnosis WLS between 1991 and 2014. Our data support survival benefits of WLS after breast and endometrial cancer diagnosis.

An Update on Screening and Prevention for Breast and Gynecological Cancers in Average and High Risk Individuals.

Breast and gynecological cancers affect almost 900,000 women and therefore most health care providers will be involved at some point in the management of women with cancer. As the prognosis of all cancers is much more favorable when diagnosed in early stages, it is imperative that all health care providers are familiar not only with current screening guidelines for the average population, but also with the identification of high risk individuals who may benefit from more intense screening as well as available interventions to prevent disease or decrease risk. The purpose of this review article is to provide relevant information to physicians and other health care providers to aid in identifying patients that are classified as "high risk" for developing breast or a gynecologic cancer, outlining what interventions exist for adequate screening and risk reduction strategies, and to provide an update on current screening guidelines for individuals at average and high risk.

Gut microbiome associations with breast cancer risk factors and tumor characteristics: a pilot study.

OBJECTIVE: To investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors. METHODS: In a pilot cross-sectional study of 37 incident breast cancer patients, fecal samples collected prior to chemotherapy were analyzed by 16S ribosomal RNA (rRNA) gene-based sequencing protocol. Alpha diversity and specific taxa by tumor characteristics and breast cancer risk factors were tested by Wilcoxon rank sum test, and by differential abundance analysis, using a zero-inflated negative binomial regression model with adjustment for total counts, age and race/ethnicity. RESULTS: There were no significant alpha diversity or phyla differences by estrogen/progesterone receptor status, tumor grade, stage, parity and body mass index. However, women with human epidermal growth factor receptor 2 positive (HER2+) (n = 12) compared to HER2- (n = 25) breast cancer showed 12-23% lower alpha diversity [number of species (OTU) p = 0.033, Shannon index p = 0.034], lower abundance of Firmicutes (p = 0.005) and higher abundance of Bacteroidetes (p = 0.089). Early menarche (ages ≤ 11) (n = 11) compared with later menarche (ages ≥ 12) (n = 26) was associated with lower OTU (p = 0.036), Chao1 index (p = 0.020) and lower abundance of Firmicutes (p = 0.048). High total body fat (TBF) (> 46%) (n = 12) compared to lower (≤ 46%) TBF was also associated with lower Chao 1 index (p = 0.011). There were other significant taxa abundance differences by HER2 status, menarche age, as well as other tumor and breast cancer risk factors. CONCLUSIONS AND RELEVANCE: Further studies are needed to identify characteristics of the human microbiome and the interrelationships between breast cancer hormone receptor status and established breast cancer risk factors.

Intravenous 5-fluoro-2'-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors.

PURPOSE: Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). METHODS: Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. RESULTS: Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. CONCLUSION: Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.

ANG1005, a Brain-Penetrating Peptide-Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases.

PURPOSE: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. PATIENTS AND METHODS: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). RESULTS: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4). CONCLUSIONS: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (n = 28).

Second-line lenvatinib in patients with recurrent endometrial cancer.

OBJECTIVE: This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes. METHODS: An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle. RESULTS: There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR. CONCLUSIONS: Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.

Efficacy of pegylated liposomal doxorubicin maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective study.

OBJECTIVE: To examine the effectiveness of pegylated liposomal doxorubicin (PLD) maintenance therapy (intravenous administration at dose 40 mg/m2 on day 1, repeated every 4 weeks) after first-line salvage chemotherapy for platinum-sensitive recurrent epithelial ovarian cancer. METHODS: This retrospective cohort study examined women with a first recurrence of platinum-sensitive epithelial ovarian cancer diagnosed between 2005 and 2015. Eligible cases had PLD maintenance following the first-line salvage chemotherapy (n = 28). Outcomes of interest included adverse events related to PLD maintenance therapy and survival outcome after the first recurrence. RESULTS: The median number of PLD maintenance cycles was 7.5 (range 2-26), and 11 (40%) women received ≥ 12 cycles. The median cumulative dose of PLD was 432.5 mg/m2 (range 120-1200 mg/m2). No women developed cardiotoxicity or secondary malignancies. There were 16 (57%) women who developed any grade of adverse events, including 3 (11%) women who developed grade 3 adverse events. There were no grade 4 adverse events. The most common adverse event was mucositis (n = 7, 25%). Dose reduction due to adverse events occurred in 14 (50%) women including 3 (11%) women with discontinuation due to toxicity. Median progression-free survival and overall survival after the initiation of PLD maintenance was 14.5 months (2-year rate 21.1%) and 51.2 months (5-year rate 43.4%), respectively. CONCLUSION: Our study suggests that PLD maintenance therapy for platinum-sensitive recurrent ovarian cancer is relatively well tolerated with the use of dose reduction to manage toxicity. Our study suggests that PLD maintenance therapy may be effective for women with platinum-sensitive recurrent epithelial ovarian cancer.

Final Analysis of the Prevention of Early Menopause Study (POEMS)/SWOG Intergroup S0230.

Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval [CI] = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio [HR] = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083.

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066-76. ©2017 AACR.

Accuracy of Contrast-Enhanced Ultrasound Compared With Magnetic Resonance Imaging in Assessing the Tumor Response After Neoadjuvant Chemotherapy for Breast Cancer.

OBJECTIVES: This pilot study compared contrast enhanced ultrasound (US) with contrast-enhanced magnetic resonance imaging (MRI) in assessing the treatment response in patients with breast cancer receiving preoperative neoadjuvant chemotherapy (NAC). METHODS: This prospective Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study included 30 patients, from January 2014 to October 2015, with invasive breast cancer detected by mammography, conventional US imaging, or both and scheduled for NAC. Informed consent was obtained. Contrast-enhanced US (perflutren lipid microspheres, 10 µL/kg) and MRI (gadopentetate dimeglumine, 0.1 mmol/kg) scans were performed at baseline before starting NAC and after completing NAC before surgery. Results of the imaging techniques were compared with each other and with histopathologic findings obtained at surgery using the Spearman correlation. Tumor size and enhancement parameters were compared for 15 patients with contrast-enhanced US, MRI, and surgical pathologic findings. RESULTS: The median tumor size at baseline was 3.1 cm on both contrast-enhanced US and MRI scans. The Spearman correlation showed strong agreement in tumor size at baseline between contrast-enhanced US and MRI (r = 0.88; P < .001) but less agreement in tumor size after NAC (r = 0.66; P = .004). Trends suggested that contrast-enhanced US (r = 0.75; P < .001) had a better correlation than MRI (r = 0.42; P = .095) with tumor size at surgery. Contrast-enhanced US was as effective as MRI in predicting a complete pathologic response (4 patients; 75.0% accuracy for both) and a non-complete pathologic response (11 patients; 72.7% accuracy for both). CONCLUSIONS: Contrast enhanced US is a valuable imaging modality for assessing the treatment response in patients receiving NAC and had a comparable correlation as MRI with breast cancer size at surgery.

Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer.

BACKGROUND: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. METHODS: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. RESULTS: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. CONCLUSION: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study.

Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. ©2016 AACR.

Value of routine staging imaging studies for patients with stage III breast cancer.

BACKGROUND AND OBJECTIVES: Routine staging imaging studies (RSIS) are optional in stage III breast cancer (BC). The impact of RSIS on treatment decisions and patient outcomes has not been extensively studied. The goal of this study was to determine whether RSIS in stage III BC affected treatment or patient outcomes. METHODS: Stage III BC patients from 2000 to 2010 were retrospectively identified. RSIS results and treatment plan in response to RSIS results were recorded. Univariate and multivariate Cox proportional hazards regression models with time-dependent covariates were used to assess associations between RSIS use and recurrence-free survival (RFS). RESULTS: Of 420 patients, 362 (86.2%) received RSIS. RSIS were negative in 264 (72.9%), indeterminate in 77 (18.3%), and positive in 21 patients (5.0%) for metastatic disease. Treatment was altered in 21 (5.8%) patients based on RSIS results (20 with metastatic disease, 1 with indeterminate disease). There was no difference in RFS with RSIS use on multivariate analysis (hazard ratio 1.3; 95% confidence interval 0.73-2.5, P = 0.32). CONCLUSIONS: Most stage III BC patients underwent RSIS, but RSIS results infrequently affected treatment decisions. There was no significant difference in RFS with RSIS use. RSIS to identify metastatic disease for stage III BC has limited value. J. Surg. Oncol. 2016;114:917-921. © 2016 Wiley Periodicals, Inc.

Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study.

BACKGROUND: Activating FGFR2 mutations are found in 10-16% of primary endometrial cancers and provide an opportunity for targeted therapy. We assessed the safety and activity of dovitinib, a potent tyrosine-kinase inhibitor of fibroblast growth factor receptors, VEGF receptors, PDGFR-ß, and c-KIT, as second-line therapy both in patients with FGFR2-mutated (FGFR2(mut)) endometrial cancer and in those with FGFR2-non-mutated (FGFR2(non-mut)) endometrial cancer. METHODS: In this phase 2, non-randomised, two-group, two-stage study, we enrolled adult women who had progressive disease after first-line chemotherapy for advanced or metastatic endometrial cancer from 46 clinical sites in seven countries. We grouped women according to FGFR2 mutation status and gave all women dovitinib (500 mg per day, orally, on a 5-days-on and 2-days-off schedule) until disease progression, unacceptable toxicity, death, or study discontinuation for any other reason. The primary endpoint was proportion of patients in each group who were progression-free at 18 weeks. For each group, the second stage of the trial (enrolment of 20 additional patients) could proceed if at least eight of the first 20 treated patients were progression free at 18 weeks. Activity was assessed in all enrolled patients and safety was assessed in all patients who received at least one dose of dovitinib. The completed study is registered with ClinicalTrials.gov, number NCT01379534. FINDINGS: Of 248 patients with FGFR2 prescreening results, 27 (11%) had FGFR2(mut) endometrial cancer. Between Feb 17, 2012, and Dec 13, 2013, we enrolled 22 patients in the FGFR2(mut) group and 31 patients in the FGFR2(non-mut) group. Seven (31·8%, 95% CI 13·9-54·9) patients in the FGFR2(mut) group and nine (29·0%, 14·2-48·0) in the FGFR2(non-mut) group were progression-free at 18 weeks. On the basis of predefined criteria, neither group continued to stage two: seven (35%) of the first 20 patients in the FGFR2(mut) group were progression free at 18 weeks, as were five (25%) of the first 20 in the FGFR2(mut) population. Rates of treatment-emergent adverse events were similar between groups and events were most frequently gastrointestinal. Overall, the most common grade 3 or 4 adverse events suspected to be related to the study drug were hypertension (nine patients; 17%) and diarrhoea (five; 9%). The most frequently reported serious adverse events suspected to be related to study drug were pulmonary embolism (four patients; 8%), vomiting (four; 8%), dehydration (three; 6%), and diarrhoea (three; 6%). Only one death was deemed to be treatment-related: one patient in the FGFR2(non-mut) group died from cardiac arrest with contributing reason of pulmonary embolism (grade 4, suspected to be study drug related) 4 days previously. INTERPRETATION: Second-line dovitinib in FGFR2(mut) and FGFR2(non-mut) advanced or metastatic endometrial cancer had single-agent activity, although it did not reach the prespecified study criteria. Observed treatment effects seemed independent of FGFR2 mutation status. These data should be considered exploratory and additional studies are needed. FUNDING: Novartis Pharmaceuticals.

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer.

PURPOSE: Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS: Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION: Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.

BACKGROUND: Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS: We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS: At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS: Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).