Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update.

PURPOSE: To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline. METHODS: An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS: Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations. RECOMMENDATIONS: Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.Additional information can be found at www.asco.org/breast-cancer-guideline.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer.

IMPORTANCE: Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown. OBJECTIVE: To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020. INTERVENTIONS/EXPOSURES: Cancer treatments, BMAs, and dental care were administered as clinically indicated. MAIN OUTCOMES AND MEASURES: Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined. RESULTS: The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02). CONCLUSIONS AND RELEVANCE: As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

PURPOSE: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance. PATIENTS AND METHODS: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662. RESULTS: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples. CONCLUSION: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

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.

Phase II randomized controlled trial of hypnosis versus progressive muscle relaxation for body image after breast or gynecologic cancer.

BACKGROUND: Sexual dysfunction, fueled by body image stress, is prevalent in women with a history of breast or gynecologic cancer. Preliminary data support that mind-body connections may improve sexual health outcomes through improving body image. OBJECTIVE: This randomized controlled trial compared hypnosis to progressive muscle relaxation (PMR). The primary outcome was body image at week 6 as measured by the Impact of Treatment Scale for women who have or have had breast or gynecologic cancer. INTERVENTIONS/METHODS: Consented participants were randomized 2:1 to hypnosis or PMR. Both arms consisted of three face-to-face sessions delivered by a trained therapist. Sessions were every 2 weeks for 6 weeks; participants practiced at home between sessions using an audio recording. RESULTS: Eighty-seven women were randomized, 59 to hypnosis and 28 to PMR. Both groups reported significant improvements on body image over time (within group effect size Cohen's d = 0.49-0.75) with no significant difference between groups (p = 0.15). Secondary outcomes were not significantly different between groups. The hypnosis group improved more in sexual satisfaction and sexual interest while the PMR group improved more in positive affect. CONCLUSIONS: Interventions facilitating mind-body connections such as hypnosis and PMR may help to improve body image. This study suggests that stress relieving strategies of hypnosis and PMR may contribute to providing a re-connection to one's body, improved positive affect, and overall better sexual health.

Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline.

PURPOSE: To provide guidance regarding best practices in the prevention and management of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. Guideline development involved a systematic review of the literature and a formal consensus process. PubMed and EMBASE were searched for studies of the prevention and management of MRONJ related to bone-modifying agents (BMAs) for oncologic indications published between January 2009 and December 2017. Results from an earlier systematic review (2003 to 2008) were also included. RESULTS: The systematic review identified 132 publications, only 10 of which were randomized controlled trials. Recommendations underwent two rounds of consensus voting. RECOMMENDATIONS: Currently, MRONJ is defined by (1) current or previous treatment with a BMA or angiogenic inhibitor, (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for longer than 8 weeks, and (3) no history of radiation therapy to the jaws or metastatic disease to the jaws. In patients who initiate a BMA, preventive care includes comprehensive dental assessments, discussion of modifiable risk factors, and avoidance of elective dentoalveolar surgery (ie, surgery that involves the teeth or contiguous alveolar bone) during BMA treatment. It remains uncertain whether BMAs should be discontinued before dentoalveolar surgery. Staging of MRONJ should be performed by a clinician with experience in the management of MRONJ. Conservative measures comprise the initial approach to MRONJ treatment. Ongoing collaboration among the dentist, dental specialist, and oncologist is essential to optimal patient care.

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

Use of Bone-Modifying Agents in Myeloma and Bone Metastases: How Recent Dosing Interval Studies Have Affected Our Practice.

The management of bone lesions from advanced solid tumors and multiple myeloma typically includes use of a bone-modifying agent to reduce the risk of skeletal-related events. Recent data demonstrate that when using zoledronic acid to reduce the risk of skeletal-related events in metastatic breast cancer, metastatic prostate cancer, and multiple myeloma, the dosing interval of zoledronic acid may be extended from every 4 weeks to every 12 weeks. The ASCO guidelines on the role of bone-modifying agents in metastatic breast cancer and multiple myeloma address zoledronic acid dosing intervals. Herein, we discuss how new data on dosing of bone-modifying agents influence our clinical practice.

Dural Cells Release Factors Which Promote Cancer Cell Malignancy and Induce Immunosuppressive Markers in Bone Marrow Myeloid Cells.

BACKGROUND: Thirty per cent of cancer patients develop spine metastases with a substantial number leading to spinal cord compression and neurological deficits. Many demonstrate a propensity toward metastasis to the posterior third of the vertebral body. The dura, the outer layer of the meninges, lies in intimate contact with the posterior border of the vertebral body and has been shown to influence adjacent bone. The effects of the dura on bone marrow and cancer cells have not been examined. Understanding the biology of spinal metastasis will provide insights into mechanisms of cancer growth and allow for new treatment strategies. OBJECTIVE: To examine the extent to which dura influences bone marrow/tumor cell metastatic characteristics. METHODS: Dura conditioned media (DCM) from primary dura was examined for the ability to stimulate tumor cell proliferation/invasion and to alter bone marrow cell populations. RNA sequencing of dural fibroblasts was performed to examine expression of cytokines and growth factors. RESULTS: DCM induced a significant increase in invasion and proliferation of multiple tumor cell lines, and of patient-derived primary spinal metastatic cells. DCM also increased the proliferation of bone marrow myeloid cells, inducing expression of immunosuppressive markers. RNA sequencing of dural fibroblasts demonstrated abundant expression of cytokines and growth factors involved in cancer/immune pathways. CONCLUSION: Factors released by primary dural cells induce proliferation of tumor cells and alter bone marrow to create a fertile environment for tumor growth. The dura therefore may play an important role in the increased incidence of metastases to adjacent bone.

Oral health-related concerns, behavior, and communication with health care providers of patients with breast cancer: impact of different treatments.

AIM: The objectives are to compare responses of breast cancer (BCa) treatment groups (chemotherapy, tamoxifen, and aromatase inhibitors (AIs) to each other and a control regarding (a) subjective oral health, (b) oral health-related behaviors, (c) oral health-related concerns, and (d) communication with health care providers. METHODS: Survey data were collected from 140 postmenopausal BCa patients and 41 healthy postmenopausal control respondents. RESULTS: BCa patients reported on average more frequent mouth sores/mucositis (5-point scale with 1 = never: 1.63 vs. 1.14; p < .01), glossadynia (1.60 vs. 1.07; p < .01), xerostomia (2.48 vs. 1.40; p < .01), and dysgeusia (2.10 vs. 1.46; p < .01) than the control respondents. Patients undergoing chemotherapy were more aware that cancer treatment can affect their oral health than patients on tamoxifen/AI (93% vs. 55%/56%; p < .001). BCa patients reported being more frequently informed by oncologists about oral health-related effects of cancer treatment than by dentists. Oncologists/nurses were more likely to communicate about oral health-related treatment effects with patients undergoing chemotherapy than patients on tamoxifen or AIs. Few BCa patients perceived dentists as knowledgeable about cancer treatment-related oral concerns and trusted them less than oncologists. CONCLUSIONS: BCa treatments impact oral health. Low percentages of BCa patients had received specific information about impacts of BCa treatments on oral health from their dentists.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To make recommendations regarding the use of bisphosphonates and other bone-modifying agents as adjuvant therapy for patients with breast cancer. Methods Cancer Care Ontario and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. Results Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with nonmetastatic breast cancer. In this guideline, postmenopausal includes patients with natural menopause or that induced by ovarian suppression or ablation. Absolute benefit is greater in patients who are at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy. Most studies evaluated zoledronic acid or clodronate, and data are extremely limited for other bisphosphonates. While denosumab was found to reduce fractures, long-term survival data are still required. Recommendations It is recommended that, if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg/d orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations. Additional information at www.asco.org/breast-cancer-adjuvant-bisphosphonates-guideline , www.asco.org/guidelineswiki , https://www.cancercareontario.ca/guidelines-advice/types-of-cancer/breast .

Oral Care: Exploring Education, Attitudes, and Behaviors Among Nurses Caring for Patients With Breast Cancer
.

BACKGROUND: Patients treated for breast cancer often experience severe oral complications, such as mucositis, xerostomia, and infections, which can result in dose reductions and treatment delays, affecting treatment outcomes.
. OBJECTIVES: The purpose of this article is to explore oncology nurses' perceptions of their educational experiences, professional attitudes, and behavior related to providing oral healthcare education to patients with breast cancer.
. METHODS: The Oncology Nursing Society sent an email to 5,000 nursing team members who cared for patients with breast cancer, requesting participation in a web-based survey; 194 responses were received, with 164 meeting study eligibility.
. FINDINGS: More oral health-related education was received during clinical experiences than during formal or continuing education. Although patient-driven oral care and diagnostic efforts were frequent, actual behavior was less frequent. No major barriers to providing oral care were indicated. Increased oral health-related education and behavior correlated with the reported importance of increased oral health education for nurses.

Dental health status and patient-reported outcomes at baseline in patients participating in the osteonecrosis of the jaw registry study, SWOG S0702.

PURPOSE: SWOG S0702 was a cohort study of patients with cancer with bone metastases due to any cancer. Using baseline data from S0702, this report characterizes the oral health and oral health-related quality of life (OHRQoL) of patients with advanced cancer. METHODS: S0702 case report forms captured dental assessment and patient-reported outcome (PRO) data. This analysis compares PRO dental discomfort with selected clinical assessments of dental health. This analysis focuses on the 2294 patients who underwent baseline dental examination prior to study registration, but also reports on the 1235 patients for whom only OHRQol data are available. Dental characteristics including the number of teeth and the presence of gingivitis and periodontal disease were examined for correlation with PRO of oral pain, interference with eating, smiling, speech, or quality of life. RESULTS: The median age of the study participants was 62. Greater than 60% of the 2294 patients with baseline dental assessments had none to mild plaque, calculus, gingivitis, or periodontal disease, suggesting that most of this cohort had good oral hygiene. However, in each of these same categories, approximately 6% had dental findings classified as severe conditions (poor oral hygiene). There was strong evidence that the presence of periodontal disease, gingivitis, and number of teeth was correlated with lower OHRQoL across multiple domains, including pain (mouth or jaw), interference with eating, smiling and speech, and overall quality of life. CONCLUSIONS: This report characterizes the oral health and OHRQoL of patients with advanced bone metastases receiving palliative therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00874211.

Phase II studies of two different schedules of dasatinib in bone metastasis predominant metastatic breast cancer: SWOG S0622.

Bone metastases from breast cancer are common, causing significant morbidity. Preclinical data of dasatinib, an oral small molecule inhibitor of multiple oncogenic tyrosine kinases, suggested efficacy in tumor control and palliation of bone metastases in metastatic breast cancer (MBC). This clinical trial aimed to determine whether treatment with either of 2 dose schedules of dasatinib results in a progression-free survival (PFS) >50 % at 24 weeks in bone metastasis predominant MBC, to evaluate the toxicity of the 2 dosing regimens, and explore whether treatment results in decreased serum bone turnover markers and patient-reported "worst pain." Subjects with bone metastasis predominant MBC were randomly assigned to either 100 mg of dasatinib once daily, or 70 mg twice daily, with treatment continued until time of disease progression or intolerable toxicity. Planned accrual was 40 patients in each arm. The primary trial endpoint was PFS, defined as time from registration to progression or death due to any cause. Median PFS for all eligible patients (79) was 12.6 weeks (95 % CI 9.1-16.7). Neither cohort met the threshold for further clinical interest. There were no significant differences in PFS by randomized treatment arm (p = 0.85). Toxicity was similar in both cohorts, with no clear trend in serum biomarkers of bone turnover or patient-reported pain. Dasatinib was ineffective in controlling bone-predominant MBC in a patient population, unselected by molecular markers. Further study of dasatinib in breast cancer should not be pursued unless performed in molecularly determined patient subsets, or rational combinations.

Self-reported oral health and quality of life of postmenopausal breast cancer survivors on aromatase inhibitors and women without cancer diagnoses: a longitudinal analysis.

INTRODUCTION: Aromatase inhibitors (AIs) are a well-established component of adjuvant therapy in postmenopausal women with hormone receptor (HR) + early stage breast cancer (BCa). We explored in an 18-month cohort study whether subjective oral health (OH), subjective periodontal health (PH), and oral health-related quality of life (OHRQoL) of postmenopausal BCa survivors on AIs differ from those of women without cancer diagnoses, and whether saliva flow, OH, PH, and OHRQoL are related. METHODS: Data were collected from 29 postmenopausal BCa survivors on AIs and 29 postmenopausal women without cancer diagnoses. Socio-demographic information, OH, PH, and OHRQoL were collected at baseline and 6, 12, and 18 months later. Unstimulated whole saliva volume per 15 min was determined by drooling. RESULTS: The two groups did not differ in background characteristics at baseline. Women on AIs had poorer OH (p = .043), PH (p = .04), and OHRQoL (p = .017), and lower saliva flow rate (p < .001) than control respondents. BCa survivors had the poorest PH at the 18-month visit. Xerostomia was correlated with OH at baseline and with OH and PH at 18 months. However, objective saliva flow rate was not correlated with OH or OHRQoL at this visit. CONCLUSIONS: This study is the first to investigate the effects of AIs on patients' subjective OH, subjective PH, and OHRQoL. The data suggest that women treated with AIs have worse OH, PH, and OHRQoL than women without cancer diagnoses. Interprofessional care is recommended so that women on AIs receive optimal supportive oral care to assure long-term OH and positive OHRQoL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01272570 https://clinicaltrials.gov/ct2/show/NCT01272570 .

Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013.

PURPOSE: The objective of this study was to determine whether the 21-gene Recurrence Score (RS) provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in the Translational Breast Cancer Research Consortium (TBCRC) 013. PATIENTS AND METHODS: TBCRC 013 was a multicenter prospective registry that evaluated the role of surgery of the primary tumor in patients with de novo stage IV breast cancer. From July 2009 to April 2012, 127 patients from 14 sites were enrolled; 109 (86%) patients had pretreatment primary tumor samples suitable for 21-gene RS analysis. Clinical variables, time to first progression (TTP), and 2-year overall survival (OS) were correlated with the 21-gene RS by using log-rank, Kaplan-Meier, and Cox regression. RESULTS: Median patient age was 52 years (21 to 79 years); the majority had hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (72 [66%]) or hormone receptor-positive/HER2-positive (20 [18%]) breast cancer. At a median follow-up of 29 months, median TTP was 20 months (95% CI, 16 to 26 months), and median survival was 49 months (95% CI, 40 months to not reached). An RS was generated for 101 (93%) primary tumor samples: 22 (23%) low risk (< 18), 29 (28%) intermediate risk (18 to 30); and 50 (49%) high risk (≥ 31). For all patients, RS was associated with TTP (P = .01) and 2-year OS (P = .04). In multivariable Cox regression models among 69 patients with estrogen receptor (ER)-positive/HER2-negative cancer, RS was independently prognostic for TTP (hazard ratio, 1.40; 95% CI, 1.05 to 1.86; P = .02) and 2-year OS (hazard ratio, 1.83; 95% CI, 1.14 to 2.95; P = .013). CONCLUSION: The 21-gene RS is independently prognostic for both TTP and 2-year OS in ER-positive/HER2-negative de novo stage IV breast cancer. Prospective validation is needed to determine the potential role for this assay in the clinical management of this patient subset.

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

Clinical predictors of long-term survival in HER2-positive metastatic breast cancer.

Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover.

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.