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We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access ( n  = 63) or usual care ( n  = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p  < 0.001) and logged into the patient’s account (61.2% vs 0% of those registered; p  < 0.001), but few sent messages to clinicians (6.1% vs 0%; p  = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p  = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p  = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p  = 0.24) and satisfaction numerically higher (15.8–16.2 vs 18.0–17.4; p  = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

PurposeFamily is often overlooked in cancer care. We developed a patient–family agenda setting intervention to engage family in cancer care communication.MethodsWe conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family “care partner.” Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks.ResultsAt baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients’ MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001).ConclusionsA patient–family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.

In breast cancer, amplification of MYC is consistently observed in aggressive forms of disease and correlates with poor prognosis and distant metastases. However, to date, a systematic analysis of MYC amplification in metastatic breast cancers has not been reported. Specifically, whether the MYC amplification status may change in metastases in comparison to the corresponding primary breast tumor, and potential variability among different metastases within the same patient have also not been assessed. We generated single patient tissue microarrays consisting of both primary breast carcinomas and multiple matched systemic metastases from 15 patients through our previously described rapid autopsy program. In total, the 15 tissue microarrays contained 145 primary tumor spots and 778 spots derived from 180 different metastases. In addition, two separate tissue microarrays were constructed composed of 10 matched primary breast cancers and corresponding solitary metastases sampled not at autopsy but rather in routine surgical resections. These two tissue microarrays totaled 50 primary tumor spots and 86 metastatic tumor spots. For each case, hormone receptor status, HER2/neu, EGFR and CK5/6 expression were assessed, and the cases were characterized as luminal, basal-like or HER2 based on published criteria. Both fluorescence in situ hybridization and immunohistochemistry for MYC was performed on all cases. Of the 25 cases, 24 were evaluable. While 4 of 24 primary tumors (16%) demonstrated MYC amplification, an additional 6 (25% of total evaluable cases) acquired MYC amplification in their systemic metastases. Of note, there was remarkably little heterogeneity in MYC copy number among different metastases from the same patient. MYC immunoreactivity was increased in metastases relative to matched primaries in the surgical cohort, although there was no perfect correlation with MYC amplification. In conclusion, amplification of MYC is a frequent event in breast cancer, but occurs more frequently as a diffuse, acquired event in metastatic disease than in the corresponding primary. These observations underscore the importance of MYC in breast cancer progression/metastasis, as well as its relevance as a potential therapeutic target in otherwise incurable metastatic disease.

PurposeAromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS.MethodsIn the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively.ResultsFrom 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density.ConclusionsCompared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0–III breast cancer received simvastatin 40 mg orally daily for 24–28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study ( P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment ( P  = 0.01 overall), particularly among post-menopausal participants ( P  = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.

The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m 2 BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand–foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.

Purpose: The objective was to compare health related quality of life (QOL) in hormone receptor negative, node-positive breast cancer patients receiving adjuvant chemotherapy to determine whether a more intensive chemotherapy regimen has an adverse effect upon QOL that is not balanced by improvements in disease control or survival. Increased physical symptoms, including fatigue and the inconvenience of the dose intensive 16-week regimen, were expected to have a negative impact on QOL. Design: QOL was measured in 163 patients, randomized to either a standard cyclophosphamide, doxorubicin and 5-flurouracil (CAF) or a 16-week multidrug regimen, using the Breast Chemotherapy Questionnaire (BCQ). The 30 item BCQ was self-administered prior to therapy, during therapy, and 4 months post treatment. Results: BCQ scores decreased (worsened) more during therapy on the 16-week regimen, median change -1.4, than on CAF, median change -0.8 (p < 0.001). By 4 months post treatment, BCQ scores were higher than pre-treatment and equal in the two arms (CAF: 8.1 and 16 weeks: 8.2, p = 0.6). Over a period of 48 months, patients on the 16-week regimen averaged 1.4 fewer months of treatment with toxicity, 4.0 more months without symptoms and 0.7 fewer months post recurrence compared to patients on the CAF regimen. Given typical values for these health states, the gain in Q-TWiST observed for the CAF regimen during treatment shifted to the 16-week regimen after 1 year, with a gain of 2.0 to 2.4 months after 4 years. Conclusions: The hypothesized negative impact of the dose intensive 16-week regimen was confirmed by the BCQ assessments. However, Q-TWiST analysis suggests a small gain for the 16-week regimen. The later results should be interpreted with caution with the limited follow-up of 4 years.

Docetaxel is primarily metabolized by CYP3A4 and susceptible to alterations in clearance by CYP3A4 inhibition and induction. Imatinib is a CYP3A4 inhibitor. A phase I study of docetaxel and imatinib in metastatic breast cancer (MBC) was conducted to test the hypothesis that imatinib decreased docetaxel clearance. Docetaxel was administered weekly × 3 with daily imatinib, repeated every 28 days; during cycle 1, imatinib was started on day 8. Docetaxel and imatinib pharmacokinetics, and hepatic CYP3A4 activity (erythromycin breath test) were evaluated during cycles 1 and 2. Toxicity and efficacy were assessed. Twelve patients were enrolled to three docetaxel/imatinib dose levels: 20 mg/m 2 /600 mg (DL1), 25 mg/m 2 /600 mg (DL2), and 25 mg/m 2 /400 mg (DL2a). Median number of prior chemotherapy regimens was 2 (range, 0–8). Toxicities were primarily observed at DL2; dose-limiting toxicities were Grade 3 transaminase elevations and diarrhea, and 5 patients had grade 2 nausea. Two patients had partial responses (7 months); two stable disease (2 and 4 months); five had progressive disease. Despite a 42% decrease in CYP3A4 activity after 3 weeks of imatinib co-administration, docetaxel clearance was unchanged. Mean ± standard deviation steady-state imatinib trough concentration (2.6 ± 1.2 μg/ml) was approximately 2.6-fold higher than previously observed in other cancer populations, and likely contributed to the poor tolerability of the combination in MBC. In conclusion, imatinib inhibited CYP3A4 but did not affect docetaxel clearance. Clinically, further investigation of this combination in MBC is not warranted due to excessive toxicities. However, these unexpected pharmacokinetic findings support further investigation of mechanisms underlying docetaxel elimination pathways.

We studied sequential dose-dense doxorubicin, paclitaxel, and 5-fluorouracil (A-T-F) before high dose chemotherapy (HDC) with autologous peripheral blood stem cell support (PBSCT). Our aims were to determine the maximum tolerated dose (MTD) of 5-FU in the dose-dense regimen and to determine the impact of dose-dense chemotherapy on HDC/PBSCT. Patients with Stage IIIB or Stage II or IIIA breast cancer with > or = 4 involved ipsilateral lymph nodes were treated with nine cycles of chemotherapy at 14-day intervals. The regimen was doxorubicin at 80 mg/m2 x 3, followed by paclitaxel at 140 mg/m2 over 96 h x 3, then 5-FU at doses of 1285, 1470, or 1655 mg/m2 by continuous intravenous infusion over 72 h x 3. Patients then underwent a G-CSF-stimulated peripheral blood stem cell (PBSC) apheresis prior to receiving HDC with autologous PBSCT. We identified 1285 mg/m2 as the MTD of 5-FU in this regimen. 5-FU-related DLTs included hand-foot syndrome, mucositis, and facial edema with somnolence. Unexpectedly, 3/19 treated patients developed congestive heart failure that prevented planned HDC. Compared to standard dose doxorubicin-containing adjuvant therapy, the dose-dense regimen also decreased CD34+ PBSC yields by about 40% (p = 0.049), requiring that 50% of patients have a supplemental bone marrow harvest. There was no difference in time to neutrophil, platelet, and red blood cell recovery after HDC. This regimen resulted in an unacceptably high rate of cardiac toxicity and is not recommended for further testing. It may be feasible to use a different schedule of 5-FU-containing dose-dense chemotherapy, particularly for the induction therapy of high-risk primary breast cancer prior to novel targeted therapies.

This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, methotrexate 100 mg/m2 on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m2 for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m2 with the vinorelbine dose held at its MTD. total of 98 courses of treatment (median of 4 per patient, range 2-8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m2, doxorubicin 40 mg/m2, and methotrexate 100 mg/m2 with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%-38%), 5 partial responses (25%, 95% confidence interval 9%-49%) and an overall response rate of 40% (95% confidence interval 19%-64%). The median survival was estimated to be 25 months from the start of chemotherapy. Vinorelbine at 25 mg/m2 can be safely administered with doxorubicin at 40 mg/m2 and methotrexate at 100 mg/m2 with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin.