Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study.

BACKGROUND: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours. METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis. RESULTS: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%). CONCLUSION: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00490139.

Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada.

Background: Trastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC. Methods: This retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE. Results: Of 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49-66); 61 (IQR 51-70) for patients with a CE. Median number of cycles was 16 (IQR 7-32); 21 (IQR 8-45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83-14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1-101, p = 0.028). Conclusion: This is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

The association between endocrine therapy use and osteoporotic fracture among post-menopausal women treated for early-stage breast cancer in Ontario, Canada.

BACKGROUND: The use of endocrine therapy for early-stage breast cancer, particularly aromatase inhibitor therapy has been associated with an increased risk of osteoporosis and fracture in clinical trials. We sought to validate this observation in real-world practice. METHODS: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012. Patients were classified by use of either an aromatase inhibitor or tamoxifen and followed until 2017 for a new diagnosis of an osteoporotic fracture. A multivariable analysis using a Cox proportional hazards model was adjusting for age, medical co-morbidities, medication use and duration of endocrine therapy. RESULTS: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor as compared to 27% with tamoxifen. Our multivariable analysis did not demonstrate any significant difference in the rate of osteoporotic fracture between patients treated with an aromatase inhibitor when compared with tamoxifen [Hazard ratio (HR) = 1.09; 95% confidence interval (CI) = 0.96-1.23, p-value = 0.18]. The 5-year rate of osteoporotic fracture for patients treated with either an aromatase inhibitor or tamoxifen was 7.5% and 6.9%, respectively. A completed sensitivity analysis did observe a decreased risk of fracture associated with tamoxifen usage over time. CONCLUSION: We could not detect a significant difference in the rate of osteoporotic fracture among patients treated with an aromatase inhibitor versus tamoxifen. Nonetheless, the risk with tamoxifen was numerically lower and significantly decreased when accounting for total duration of endocrine therapy.

Predictive Significance of an Optimized Panel for Basal-like Breast Cancer: Results from the Canadian Cancer Trials Group MA.5 and MA.12 Phase III Clinical Trials.

PURPOSE: Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials. EXPERIMENTAL DESIGN: Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin+ or INPP4B-) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12. RESULTS: Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72-3.10] when compared with non-basal (nestin- and INPP4B+) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54-1.04; P interaction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12-1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45-0.98; P = 0.04), although the interaction test was not significant. CONCLUSIONS: The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.

Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D).

AIM: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. PATIENTS AND METHODS: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). RESULTS: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups. CONCLUSION: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.

The association between endocrine therapy use and dementia among post-menopausal women treated for early-stage breast cancer in Ontario, Canada.

PURPOSE: The association between endocrine therapy and risk of dementia remains uncertain. We investigated the association between adjuvant endocrine therapy for breast cancer and risk of developing dementia in a real-world, population-based study. METHODS: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012 with follow-up until 2017. Patients were classified by the use of either an aromatase inhibitor or tamoxifen and followed to estimate the unadjusted cumulative incidence of developing dementia. A multivariable Cox proportional hazards model was created adjusting for age, income quintile, medical co-morbidities, and duration of endocrine therapy. RESULTS: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor and 27% with tamoxifen. Our multivariable analysis showed a lower rate of dementia in patients treated with an aromatase inhibitor as compared to tamoxifen [Hazard ratio (HR) = 0.88, 95% confidence interval (CI): 0.78-0.98, p-value = .02) at a median follow-up of 5.9 years. The 5-year dementia rate among patient treated with either an aromatase inhibitor or tamoxifen was 7.4% and 9.2% respectively. Older age, previous history of ischemic heart disease, diabetes, hypertension and history of stroke were all significantly associated with the development of dementia. CONCLUSION: Aromatase inhibitor therapy was associated with a decreased incidence of dementia as compared to treatment with tamoxifen among post-menopausal women with early stage breast cancer. Further prospective studies with longer-term follow-up investigating the neurocognitive effects of endocrine therapy are warranted.

Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study.

Studies have suggested that women with elevated BMI or 25-OH vitamin D levels may derive less benefit from AIs versus tamoxifen. We prospectively investigated whether high BMI or 25-OH vitamin D levels were associated with higher estrogen levels in post-menopausal women receiving standard adjuvant letrozole (2.5 mg/day). Furthermore, we evaluated whether an increased dose of letrozole resulted in lower serum estrogens in women with BMI > 25 kg/m2. Correlation between entry BMI and day 29 serum biomarkers (estrogens, 25-OH vitamin D, insulin, CRP, leptin) was assessed in all patients. On day 29, participants with BMI > 25 kg/m2 switched to letrozole 5 mg/day for 4-weeks and blood was drawn upon completion of the study. The change in serum estrogen levels was assessed in these patients (BMI > 25 kg/m2). 112 patients completed days 1-28. The Pearson correlations of estradiol and estrone with BMI or serum 25-OH vitamin D levels were near zero (-0.04 to 0.07, p = 0.48-0.69). Similar results were obtained for correlation with markers of obesity (insulin, CRP, and leptin) with estradiol and estrone (-0.15 to 0.12; p = 0.11-0.82). Thirty-one patients (BMI > 25 kg/m2) completed the interventional component; Increasing the dose of letrozole did not further reduce estradiol or estrone levels (change 0.1 and 0.4 pmol/L respectively; p = 0.74 and 0.36). There was no observed association between markers of obesity (BMI, insulin, leptin, and CRP), serum 25-OH vitamin D levels and estradiol or estrone levels. Additionally, an increased dose of letrozole did not further reduce estradiol or estrone levels compared to the standard dose.

Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx.

PURPOSE: Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS: Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS: FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION: Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

The LISA randomized trial of a weight loss intervention in postmenopausal breast cancer.

Obesity has been associated with poor breast cancer (BC) outcomes. We investigated whether a standardized, telephone-based weight loss lifestyle intervention in the adjuvant setting would impact BC outcomes. We conducted a multicenter trial randomizing women 1:1 to mail-based educational material alone (control) or combined with a standardized, telephone-based lifestyle intervention that focused on diet, physical activity, and behavior and involved 19 calls over 2 years to achieve up to 10% weight loss. In all, 338 (of 2150 planned) T1-3, N0-3, M0 hormone receptor positive BC patients with body mass index (BMI) ≥24 kg/m2 receiving adjuvant letrozole were randomized (enrolment ended due to funding loss). The primary outcome was disease-free survival (DFS); secondary outcome was Overall Survival (OS). At 8 years' median follow-up, in a planned analysis, DFS and OS were compared using the Kaplan-Meier method. Baseline BMI and other characteristics were similar between study arms. In all, 22 of 171 (12.9%) in the lifestyle intervention arm versus 30 of 167 (18.0%) in the education had DFS events; the hazard ratio (HR) was 0.71 (95% confidence interval [CI]: 0.41-1.24, p = 0.23). Although loss of funding reduced sample size, we view these hypothesis generating results as compatible with our hypothesis of a potential beneficial effect of a lifestyle intervention on DFS. They provide support for completion of ongoing randomized controlled trials of the effect of lifestyle interventions in BC outcomes.

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy.

Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%-68%), and 44% (95%CI 22%-69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23-9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%-81%) and 0% (95%CI 0%-31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.

Incidence of Brain Metastases in Nonmetastatic and Metastatic Breast Cancer: Is There a Role for Screening?

BACKGROUND: Current National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend against screening breast cancer patients for asymptomatic brain metastases. Because brain metastases are a major cause of morbidity and mortality from breast cancer, we undertook a literature review to ascertain whether there might be a role for brain metastases screening in high-risk patient subgroups. MATERIALS AND METHODS: A literature search was conducted on the OvidSP platform in the MedLine database, using MeSH terms and subject headings related to breast cancer, brain metastases, and incidence. The search was conducted without language or publication restrictions, and included articles indexed from January 1, 2006 to June 10, 2018. Experimental and observational studies that reported the incidence of brain metastases in patients with nonmetastatic or metastatic breast cancer were included. RESULTS: One hundred seventy studies were identified, with 33 included in the final analysis. Among nonmetastatic breast cancer patients, incidence of brain metastases as site of first recurrence per year of median follow-up ranged from 0.1% to 3.2%. Although incidence of brain metastases was much higher among the metastatic breast cancer population overall, it was particularly high among metastatic HER2-overexpressing (HER2+) and triple-negative populations, ranging between 22% and 36% for the former, and 15%-37% for the latter in the absence of screening. CONCLUSION: In patients with nonmetastatic breast cancer, screening for asymptomatic brain metastases cannot currently be justified. However, due to the high incidence of brain metastases among patients with metastatic HER2+ and triple-negative breast cancer, studies to determine the value of screening for brain metastases should be undertaken in these subgroups.

Factors associated with endocrine therapy adherence among post-menopausal women treated for early-stage breast cancer in Ontario, Canada.

PURPOSE: Adherence to adjuvant endocrine therapy among post-menopausal breast cancer patients is an important survivorship care issue. We explored factors associated with endocrine therapy adherence and survival in a large real-world population-based study. METHODS: We used health administrative databases to follow women (aged ≥ 66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2010. Adherence was measured by medical possession ratio (MPR) and characterized as low (< 39% MPR), intermediate (40-79% MPR), or high (≥ 80% MPR) over a 5-year period. We investigated factors associated with adherence using a multinomial logistic regression model. Factors associated with all-cause mortality (5 years after starting endocrine therapy) were investigated using a multivariable Cox proportional hazards model. RESULTS: We identified 5692 eligible patients starting adjuvant endocrine therapy who had low, intermediate, and high adherence rates of 13% (n = 749), 13% (n = 733), and 74% (n = 4210), respectively. Lower rates of adherence were associated with increased age [low vs. high adherence: odds ratio (OR) 1.03, 95% CI 1.02-1.05 (per year); intermediate vs. high adherence: OR 1.02, 95% CI 1.01-1.04 (per year)]. High adherence was associated with previous use of adjuvant chemotherapy (low versus high adherence OR 0.42, 95% CI 0.30-0.59) and short-term follow-up with a medical oncologist within 4 months of starting endocrine therapy (low versus high adherence OR 0.83, 95% CI 0.69-0.99). Unadjusted analysis showed increased survival among patients with high endocrine therapy adherence. However, an independent association was no longer clearly detected after controlling for confounders. CONCLUSION: Interventions to improve adjuvant endocrine therapy adherence are warranted. Non-adherence may be a more significant issue among elderly patients. Short-term follow-up visit by a patient's medical oncologist after starting endocrine therapy may help to improve compliance.

Identifying research priorities in the treatment of patients with early breast cancer: from the patient perspective.

In identifying research priorities it is important to take the needs and prospective of patients with breast cancer into account.

Influenza Vaccine Effectiveness Among Patients With Cancer: A Population-Based Study Using Health Administrative and Laboratory Testing Data From Ontario, Canada.

PURPOSE: Seasonal influenza vaccination is recommended for patients with cancer despite concerns of disease or treatment-associated immunosuppression. The objective of this study was to evaluate vaccine effectiveness (VE) against laboratory-confirmed influenza for patients with cancer. PATIENTS AND METHODS: We conducted an observational test-negative design study of previously diagnosed patients with cancer 18 years of age and older who underwent influenza testing during the 2010-2011 to 2015-2016 influenza seasons in Ontario, Canada. We linked individual-level cancer registry, respiratory virus testing, and health administrative data to identify the study population and outcomes. Vaccination status was determined from physician and pharmacist billing claims. We used multivariable logistic regression to estimate VE, adjusting for age, sex, rurality, income quintile, cancer characteristics, chemotherapy exposure, comorbidities, previous health care use, influenza season, and calendar time. RESULTS: We identified 26,463 patients with cancer who underwent influenza testing, with 4,320 test-positive cases (16%) and 11,783 (45%) vaccinated. Mean age was 70 years, 52% were male, mean time since diagnosis was 6 years, 69% had solid tumor malignancies, and 23% received active chemotherapy. VE against laboratory-confirmed influenza was 21% (95% CI, 15% to 26%), and VE against laboratory-confirmed influenza hospitalization was 20% (95% CI, 13% to 26%). For patients with solid tumor malignancies, VE was 25% (95% CI, 18% to 31%), compared with 8% (95% CI, -5% to 19%) for patients with hematologic malignancies (P = .015). Active chemotherapy usage did not significantly affect VE, especially among patients with solid tumor cancer. CONCLUSION: Our results support recommendations for influenza vaccination for patients with cancer. VE was decreased for patients with hematologic malignancies, and there was no significant difference in VE among patients with solid tumor cancer receiving active chemotherapy. Strategies to optimize influenza prevention among patients with cancer are warranted.

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.

BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

A priori prediction of breast tumour response to chemotherapy using quantitative ultrasound imaging and artificial neural networks.

We demonstrate the clinical utility of combining quantitative ultrasound (QUS) imaging of the breast with an artificial neural network (ANN) classifier to predict the response of breast cancer patients to neoadjuvant chemotherapy (NAC) administration prior to the start of treatment. Using a 6 MHz ultrasound system, radiofrequency (RF) ultrasound data were acquired from 100 patients with biopsy-confirmed locally advanced breast cancer prior to the start of NAC. Quantitative ultrasound mean parameter intensity and texture features were computed from the tumour core and margin, and were compared to the clinical/pathological response and 5-year recurrence-free survival (RFS) of patients. A multi-parametric QUS model in conjunction with an ANN classifier predicted patient response with 96 ± 6% accuracy, and a 0.96 ± 0.08 area under the receiver operating characteristic curve (AUC), compared to 65 ± 10 % accuracy and 0.67 ± 0.14 AUC achieved using a K-Nearest Neighbour (KNN) algorithm. A separate ANN model predicted patient RFS with 85 ± 7% accuracy, and a 0.89 ± 0.11 AUC, whereas the KNN methodology achieved a 58 ± 6 % accuracy and a 0.64 ± 0.09 AUC. The application of ANN for classifying patient response based on tumour QUS features performs well in terms of predicting response to chemotherapy. The findings here provide a framework for developing personalized a priori chemotherapy selection for patients that are candidates for NAC, potentially resulting in improved patient treatment outcomes and prognosis.

A meta-analysis of clinical benefit rates for fulvestrant 500 mg vs. alternative endocrine therapies for hormone receptor-positive advanced breast cancer.

BACKGROUND: Fulvestrant, a selective estrogen receptor degrader, is approved for first- and second-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (ABC). METHODS: Meta-analysis of randomized controlled trials (RCTs) evaluating fulvestrant 500 mg in postmenopausal hormone receptor-positive ABC, to evaluate differences in clinical benefit rate (CBR; proportion of patients experiencing best overall response of complete response, partial response, or stable disease for ≥ 24 weeks) between fulvestrant 500 mg and comparator endocrine therapies. Odds ratios (OR) and 95% confidence intervals (CI) for CBR were calculated; fixed effects (FE) models were constructed (first- and second-line data, alone and combined). RESULTS: Six RCTs were included. Four studies evaluated fulvestrant 500 mg vs. fulvestrant 250 mg; two evaluated fulvestrant 500 mg vs. anastrozole 1 mg. In total, 1054 and 534 patients were included (first- and second-line treatment, respectively). Analysis of OR and 95% CI of CBR by therapy line favored fulvestrant 500 mg vs. comparator therapy. Assessing all results combined in the FE model indicated significant improvement in CBR with fulvestrant 500 mg vs. comparator treatments (OR 1.33; 95% CI 1.13-1.57; p = 0.001). Restricting the FE model to therapy line demonstrated significant improvement in CBR vs. comparator treatments (OR 1.33; 95% CI 1.02-1.73; p = 0.035) for first-line, and a trend to improvement vs. comparator treatments (OR 1.27; 95% CI 0.90-1.79; p = 0.174) for second-line. CONCLUSIONS: In postmenopausal patients with hormone receptor-positive ABC, fulvestrant 500 mg first-line was associated with significantly greater CBR (more patients benefiting from treatment) vs. comparator endocrine therapy.

Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients.

Background: In premenopausal patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown. Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor-positive and -negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided. Results: A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor-positive disease. Median age was 43 (interquartile range = 38-47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab→lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor-positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor-negative patients. Conclusions: In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor-positive/HER2-positive early breast cancer patients.

Breast Cancer Screening: Beyond Mortality.

Traditionally, the effectiveness of breast cancer screening has been measured in terms of reducing the number of deaths attributable to breast cancer. Other metrics such as the number of life-years or quality-adjusted life-years gained through screening may be more relevant and certainly may better reflect the important burden of the disease on younger women, their families, and society. The effects of earlier detection of breast cancer in reducing morbidities associated with treatment have often also been neglected. In addition, the harms and limitations associated with cancer screening have been poorly quantified and are seldom put into perspective vis-à-vis the benefits. Here, these alternative measures will be discussed and quantified.