Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with ...HER2-positive metastatic breast cancer (MBC).
Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR).
Sixty-four patients (43 patients in the second-line or greater setting advanced MBC; 21 patients in the first-line setting first-line MBC) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively).
T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.
The treatment of stage III non-small-cell lung cancer has evolved over the last two decades, with combined-modality therapy the current standard of care. As a result, intermediate and long-term ...survival has improved for patients in this common stage category, compared to the poor outcomes achieved with the historical standard of once-daily radiation therapy alone. This review summarizes two decades of clinical research regarding bimodality and trimodality approaches for the heterogenous stage subsets within the stage III designation, discusses the rationale and status of prophylactic brain irradiation, and concludes with perspectives on progress and future directions. Chemotherapy plus radiotherapy given concurrently is the optimal treatment for the group of patients with advanced stage III disease. The potential role of a surgical resection following chemotherapy (with or without radiation) in this setting is still controversial. The only subsets for which trimodality treatments are clearly preferred include T4N0-1 disease and superior sulcus tumors. The other major stage III subgroup has a minimal disease burden with low tumor volume and/or microscopic N2 disease, thus technically could undergo a surgical resection upfront. Induction chemotherapy before surgery may yield a survival advantage, although the phase III trials in this area are not conclusive. Given the marked survival benefit from adjuvant chemotherapy after surgery in even earlier stages of non-small-cell lung cancer, the proper sequence of surgery and chemotherapy (before v after surgery) remains an important unresolved question in this subgroup. Furthermore, how to incorporate radiation therapy, as well as whether it should be given at all in this subset of patients, are other important issues actively under study in ongoing trials.
More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth ...of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib.
To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.
Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens.
Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo).
Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung FACT-L instrument) and tumor regression (>50% decrease in lesion size on imaging studies).
Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval CI, 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006).
Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.
Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study ...was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity.
Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm.
In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 0.83, 1.13, p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 0.23, 0.93, p = 0.001), phenylalanine (β = 0.54 0.19, 0.89, p = 0.002), tyrosine (β = 0.57 0.23, 0.91, p = 0.001), and valine (β = 0.58 0.24, 0.92, p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality.
This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.
Women of African ancestry (AA) have lower WBC counts and are more likely to have treatment delays and discontinue adjuvant breast cancer therapy early compared with white women. We assessed the ...association between race and treatment discontinuation/delay, WBC counts, and survival in women enrolled onto breast cancer clinical trials.
AA and white women from Southwest Oncology Group adjuvant breast cancer trials (S8814/S8897) were matched by age and protocol. Only the treatment arms in which patients were scheduled to receive six cycles of chemotherapy were analyzed.
A total of 317 pairs of patients (n = 634) were analyzed. At baseline, AA women had higher body-surface area (P < .0001) and lower WBC (P = .0009). AA women were more likely to have tumors that were > or = 2 cm (P = .01) and hormone receptor negative (P < .0001). AA women, versus white women, were marginally more likely to discontinue treatment early (11% v 7%, respectively; P = .07) or have one or more treatment delays (85% v 79%, respectively; P = .07) and were significantly more likely to experience the combined end point (discontinuation/delay; 87% v 81%, respectively; P = .04). The mean relative dose-intensity (RDI) was similar for both groups (87% in AA women v 86% in white women); however, overall, 43% had an RDI of less than 85%. After adjusting for baseline WBC and prognostic factors in a multivariate model, AA women had worse disease-free survival (hazard ratio HR = 1.56; 95% CI, 1.15 to 2.11; P = .005) and overall survival (HR = 1.95; 95% CI, 1.36 to 2.78; P = .0002). The inclusion of RDI and treatment delivery/quality in the regression had little impact on the results.
On cooperative group breast cancer trials, AA and white women had similar RDIs, but AA women were more likely to experience early discontinuation or treatment delay. Despite correcting for these factors and known predictors of outcome, AA women still had worse survival.
To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer.
A 2 × 2 factorial design was used to test two hypotheses: (1) ...that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome.
Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40).
Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.
Serum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC ...treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).
sTK1 was assessed in 1,726 serums baseline (BL), cycles 2, 3, 4, and 7 using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests, and Cox regression.
BL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43-2.16);
< 0.0001 and OS median 30 vs. 58 months, HR = 2.38; 95% CI (1.91-2.98);
< 0.0001. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone median 46 vs. 21 months, HR = 0.58; 95% CI (0.38-0.87);
= 0.0087. Patients with low sTK1 had no difference in outcomes by therapy (
= 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS at cycle 2: PFS HR = 1.70, 95% CI (1.34-2.17);
< 0.0001, OS HR = 2.51, 95% CI (1.93-3.26);
< 0.0001.
High sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.
A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit.
...To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone.
In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019.
The adjuvant chemotherapy regimen was selected by the treating physician.
Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival IDFS).
Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error SE, 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%).
The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.
ClinicalTrials.gov identifier: NCT00310180.
Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. However, the burden is not evenly distributed, and, according to the best ...available data, there are large variations in the incidence, mortality, and survival between different countries and regions and within specific regions. Many complex factors underlie these variations, including population structure (eg, age, race, and ethnicity), lifestyle, environment, socioeconomic status, risk factor prevalence, mammography use, disease stage at diagnosis, and access to high-quality care. We review recent breast cancer incidence and mortality statistics and explore why these vary so greatly across the world. Further research is needed to fully understand the reasons for variations in breast cancer outcomes. This will aid the development of tailored strategies to improve outcomes in general as well as the standard of care for underserved populations and reduce the burden of breast cancer worldwide.
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