Adjuvant platinum versus capecitabine for residual, invasive, triple-negative breast cancer: Patient-reported outcomes in ECOG-ACRIN EA1131.

BACKGROUND: Patient-reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment-associated adverse events (AEs) compared with clinician-rated AEs. The authors present PROs assessing health-related quality of life (HRQoL) and treatment-related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391). METHODS: Participants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) and the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI-16 treatment side-effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t-tests or the Wilcoxon rank-sum test, and proportions were compared by using the χ2 test. RESULTS: Two hundred ninety-six of 330 eligible patients provided PROs. The mean NFBSI-16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, -0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05). CONCLUSIONS: Despite the similar frequency of clinician-rated AEs, PROs identified greater on-treatment symptom burden with capecitabine and complemented clinician-rated AEs by characterizing patients' experiences during chemotherapy.

Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial).

AIMS: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. METHODS: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. RESULTS: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. CONCLUSIONS: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. CLINICAL TRIAL REGISTRATION: NCT02614794.

Circulating tumor cell number and endocrine therapy index in ER positive metastatic breast cancer patients.

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). The CTC-endocrine therapy index (CTC-ETI), consisting of CTC-ER (estrogen receptor), BCL2, human epidermal growth factor receptor (HER2), and Ki67 expression, might predict resistance to endocrine therapy (ET) in patients with ER-positive MBC. One hundred twenty-one patients with ER-positive/HER2-negative MBC initiating a new ET after ≥1 lines of ET were enrolled in a prospective, multi-institutional clinical trial. CTC-ETI and clinical/imaging follow-up were performed at baseline and serial time points. Progression-free survival (PFS) and rapid progression (RP; determined at the 3-month time point) were primary endpoints. Associations with clinical outcomes used logrank and Fisher's exact tests. At baseline, 36% (38/107) of patients had ≥5 CTC/7.5 ml whole blood (WB). Patients with ≥5 vs. <5 CTC/7.5 ml WB had significantly worse PFS (median 3.3 vs. 5.9 months, P = 0.03). Elevated CTC at 1 month was associated with even worse PFS (1.9 vs. 5.0 months from the 1-month sample, P < 0.001). Low, intermediate, and high CTC-ETI were observed in 71 (66%), 8 (8%), and 28 (26%) patients, with median PFS of 6.9, 8.5, and 2.8 months, respectively (P = 0.008). Patients with high vs. low CTC and CTC-ETI more frequently experienced RP (CTC: 66% vs. 41%; P = 0.03; CTC-ETI: 79% vs. 40%; P = 0.002). In conclusion, CTC enumeration and the CTC-ETI assay are prognostic at baseline and follow-up in patients with ER-positive/HER2-negative MBC starting new ET. CTC at first follow-up might identify a group of patients with ER-positive MBC that could forego ET, but CTC-ETI did not contribute further.

Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131.

PURPOSE: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. PATIENTS AND METHODS: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. RESULTS: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. CONCLUSION: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

Efficacy and Safety of Weekly Paclitaxel With or Without Oral Alisertib in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance: Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. Objective: To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). Design, Setting, and Participants: In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019. Main Outcomes and Measures: The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. Results: A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis. Conclusions and Relevance: This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC. Trial Registration: ClinicalTrials.gov Identifier: NCT02187991.

Use of the blood substitute HBOC-201 in critically ill patients during sickle crisis: a three-case series.

BACKGROUND: Red blood cell (RBC) transfusion is an important treatment modality during severe sickle cell crisis (SCC). SCC patients who refuse, or cannot accept, RBCs present a unique challenge. Acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) might be an alternative for critically ill patients in SCC with multiorgan failure due to life-threatening anemia. HBOC-201 (HbO2 Therapeutics) has been administered to more than 800 anemic patients in 22 clinical trials, but use of any HBOCs in critically ill sickle cell patients with organ failure is exceedingly rare. In the United States, HBOC-201 is currently only available for expanded access. CASE REPORT: We report three cases of HBOC-201 administered to critically ill sickle cell disease patients in SCC with multiorgan failure, either who refused RBCs (Jehovah's Witnesses) or for whom compatible RBCs were not available. RESULTS: Two patients received more than 20 units of HBOC-201, while the other received 6. The 27 units used in the third case equals the largest volume a patient has successfully received to date. All three patients survived to hospital discharge. CONCLUSION: These reports suggest that blood substitutes such as HBOC-201 can provide an oxygen bridge in SCC with multiorgan failure, until corpuscular Hb levels recover to meet metabolic demand, and highlight the compelling biochemical properties that warrant further investigation.

Is bortezomib, a proteasome inhibitor, effective in treating cancer-associated weight loss? Preliminary results from the North Central Cancer Treatment Group.

BACKGROUND: Weight loss predicts a poor prognosis for cancer patients, and previous studies have implicated the ubiquitin-proteasome pathway as a major mediator of cancer-associated weight loss. The recent emergence of bortezomib, a proteasome inhibitor, now allows testing on whether proteasome inhibition is effective therapy for cancer-associated weight loss. METHODS: This study represents a subanalysis from two prior antineoplastic trials in patients with adenocarcinoma of the pancreas. The first included 46 patients with metastatic pancreatic cancer who were treated with single-agent bortezomib (intravenous doses of 1.5 or 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle). The second included 42 patients with pancreatic cancer treated with single-agent octreotide (200 or 500 microg subcutaneously three times a day). The FACT-C questionnaire provided appetite and related data for bortezomib-treated patients. Serial weight data were available from both trials. Such data from the octreotide trial were utilized for comparative purposes because the latter holds no track record in treating cancer-associated weight loss. RESULTS: Bortezomib- and octreotide-treated patients were roughly comparable at baseline, and neither agent demonstrated notable antineoplastic effects. FACT-C data suggested stable appetite, but high patient dropout rates invite caution in interpretation. For example, in response to "I have a good appetite," mean scores for bortezomib-treated patients were 45 at baseline (n=42), 45 at the end of cycle 1 (n=26), and 44 at the end of cycle 2 (n=9). In contrast, weight data appeared more straightforward to interpret: direct comparisons of mean change in weight from baseline between bortezomib- and octreotide-treated patients showed no significant differences between groups. CONCLUSIONS: These preliminary results suggest that bortezomib shows negligible favorable effects on cancer-associated weight loss in patients with metastatic pancreatic cancer. We conclude that further study of bortezomib specifically in this setting and for this indication is not warranted.

A phase II study of topical ceramides for cutaneous breast cancer.

PURPOSE: Short chain ceramides induce tumor cell apoptosis in preclinical models. Limited therapeutic options for patients with cutaneous breast cancer prompted the testing of these sphingolipids in patients with this disease. PATIENTS AND METHODS: Twenty-five patients with refractory, cutaneous breast cancer were treated twice a day with a 1% mixture of topical C2 and C6 ceramides administered in a 1:1 ratio. For the first 8 weeks, patients were not allowed to receive other antineoplastic therapy. In addition to tumor status and toxicity assessment throughout the trial, skin biopsies for evidence of apoptosis and quality of life questionnaires (FACT-BR) were completed at baseline and 1 month. RESULTS: Only one patient manifested a partial response with topical ceramides, yielding a response rate of 4% (90% confidence interval 0, 17.6%). Median cutaneous progression-free survival was 2 months. The topical ceramides were also well tolerated, with no grade 3 or 4 toxicity reported. None of the six patients who underwent serial skin biopsies showed increased tumor cell apoptosis morphologically or by the modified TUNEL assay. CONCLUSION: To our knowledge, this trial is one of the first clinical investigations of short chain ceramides. This trial's results are not promising enough to merit further study of ceramides in the manner prescribed.