Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with ...persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS).
Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2).
Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001).
This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.
The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 ...(HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.
In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival.
A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer breast cancer or another type, or death, 1.02; 95% confidence interval CI, 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.
Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).
The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be ...more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.
Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome.
The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval CI, 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.
The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).
Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors and often result in therapy discontinuation. Small studies suggest that acupuncture may decrease aromatase ...inhibitor-related joint symptoms.
To determine the effect of acupuncture in reducing aromatase inhibitor-related joint pain.
Randomized clinical trial conducted at 11 academic centers and clinical sites in the United States from March 2012 to February 2017 (final date of follow-up, September 5, 2017). Eligible patients were postmenopausal women with early-stage breast cancer who were taking an aromatase inhibitor and scored at least 3 on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain).
Patients were randomized 2:1:1 to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57) group. True acupuncture and sham acupuncture protocols consisted of 12 acupuncture sessions over 6 weeks (2 sessions per week), followed by 1 session per week for 6 weeks. The waitlist control group did not receive any intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52.
The primary end point was the 6-week BPI-WP score. Mean 6-week BPI-WP scores were compared by study group using linear regression, adjusted for baseline pain and stratification factors (clinically meaningful difference specified as 2 points).
Among 226 randomized patients (mean SD age, 60.7 8.6 years; 88% white; mean SD baseline BPI-WP score, 6.6 1.5), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20-1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24-1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01).
Among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related arthralgias, true acupuncture compared with sham acupuncture or with waitlist control resulted in a statistically significant reduction in joint pain at 6 weeks, although the observed improvement was of uncertain clinical importance.
ClinicalTrials.gov Identifier: NCT01535066.
Purpose Adherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration ...approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo. Methods This randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of ≥ 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a ≥ 2-point decrease from baseline. Results Of 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, -1.24 to -0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine-treated group (78% v 50%); rates of grade 3 adverse events were similar. Conclusion Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities.
Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ...ALC may be effective for the prevention and treatment of CIPN.
A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index TOI), fatigue (Functional Assessment of Chronic Illness Therapy FACIT -Fatigue), and NTX grade.
A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo.
There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.
We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been ...randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.
We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.
Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval CI, 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.
The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).
Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus ...platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like.
S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1–14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905.
Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6–20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3–9·2) in the cisplatin plus veliparib group and 6·4 months (4·3–8·2) in the cisplatin plus placebo group (HR 0·79 95% CI 0·38–1·67; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3–7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3–5·0) in the cisplatin plus placebo group (HR 0·57 95% CI 0·37–0·88; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5–4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2–4·4) in the cisplatin plus placebo group (HR 0·89 95% CI 0·60–1·33; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 46% of 155 patients in the cisplatin plus veliparib group vs 29 20% of 147 in the cisplatin plus placebo group), leukopenia (42 27% vs 11 7%), anaemia (35 23% vs 12 8%), and thrombocytopenia (29 19% vs four 3%). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure).
The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer.
National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.
Abstract
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes. Acetyl-L-carnitine (ALC) was unexpectedly found to increase CIPN in a ...randomized trial. We investigated the long-term patterns of CIPN among patients in this trial.
Methods
S0715 was a randomized, double-blind, multicenter trial comparing ALC (1000 mg three times a day) with placebo for 24 weeks in women undergoing adjuvant taxane-based chemotherapy for breast cancer. CIPN was measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at weeks 12, 24, 36, 52, and 104. We examined NTX scores over two years using linear mixed models for longitudinal data. Individual time points were examined using linear regression. Regression analyses included stratification factors and the baseline score as covariates. All statistical tests were two-sided.
Results
Four-hundred nine subjects were eligible for evaluation. Patients receiving ALC had a statistically significantly (P = .01) greater reduction in NTX scores (worse CIPN) of –1.39 points (95% confidence interval CI = –2.48 to –0.30) than the placebo group. These differences were particularly evident at weeks 24 (–1.68, 95% CI = –3.02 to –0.33), 36 (–1.37, 95% CI = –2.69 to –0.04), and 52 (–1.83, 95% CI = –3.35 to –0.32). At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline. For both treatment groups, 104-week NTX scores were statistically significantly different compared with baseline (P < .001).
Conclusions
For both groups, NTX scores were reduced from baseline and remained persistently low. Twenty-four weeks of ALC therapy resulted in statistically significantly worse CIPN over two years. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Until then, the potential efficacy and harms of commonly used supplements should be rigorously studied.
Abstract
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.
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