Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment ...domains.
We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome-Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic
nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined.
In total, N = 23,296 patients (women, 8,838 37.9%; men, 14,458 62.1%) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio OR = 1.34; 95% CI, 1.27 to 1.42;
< .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78;
< .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01;
< .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found.
The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.
When a genetic test was used to assess prognosis, women with midrange scores were found to have similar outcomes after adjuvant treatment with either endocrine therapy alone or chemotherapy plus ...endocrine therapy.
The combination of anastrozole and fulvestrant — which interfere with estrogen signaling by distinct mechanisms — increases progression-free and overall survival as compared with anastrozole alone or ...anastrozole followed by fulvestrant in women with HR-positive breast cancer.
Endocrine therapy plays a central role in the treatment of hormone-receptor (HR)–positive metastatic breast cancer.
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Selective aromatase inhibitors, such as anastrozole, letrozole, and exemestane, lower the estrogen level and are used as first-line endocrine treatments of HR-positive metastatic disease, owing to their superiority over tamoxifen.
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Fulvestrant (Faslodex, AstraZeneca) is an analogue of estradiol that down-regulates the estrogen receptor by disrupting estrogen-receptor dimerization and accelerating degradation of the unstable fulvestrant–estrogen-receptor complex.
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This effect leads to reduced cross-talk between the estrogen receptor and estrogen-independent growth factor signaling, thus delaying resistance to hormone therapy.
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Clinically, fulvestrant at a dose of 250 mg monthly . . .
Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab ...adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer.
A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks.
At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab CRxT
89.2% with CRx alone; hazard ratio HR, 0.98; 95% CI, 0.76 to 1.25;
= .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50;
= .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95;
= .15). There were no unexpected toxicities from the addition of trastuzumab to CRx.
The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non-small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a ...maintenance setting in stage III disease.
Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m(2) on days 1 and 8 plus etoposide 50 mg/m(2) on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m(2). Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease.
Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo.
In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.
Summary Background The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts ...little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio HR 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. Interpretation The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding National Cancer Institute and Genomic Health.
Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal ...women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.
Summary Background Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection ...after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Methods Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and 29–33) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00002550. Findings 202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23·6 months (IQR 9·0–not reached) in group 1 versus 22·2 months (9·4–52·7) in group 2 (hazard ratio HR 0·87 0·70–1·10; p=0·24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0·63 0·36–1·10; p=0·10). With N0 status at thoracotomy, the median OS was 34·4 months (IQR 15·7–not reached; 19 point estimate 41% patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12·8 months (5·3–42·2) vs 10·5 months (4·8–20·6), HR 0·77 0·62–0·96; p=0·017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 38% and 20 10%, respectively) and group 2 (80 41% and 44 23%, respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Interpretation Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. Funding National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
Summary Background Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer ...and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy. Methods The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00053898 , and is complete. Findings Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2–10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 95% CI 0·56–0·96, p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism—a known side-effect of tamoxifen—for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group. Interpretation Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ. Funding US National Cancer Institute and AstraZeneca Pharmaceuticals LP.
Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with ...HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.
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