Understanding the Needs of Patients with Metastatic Breast Cancer: Results of the Make Your Dialogue Count Survey.

With more patients with metastatic breast cancer (MBC) living longer, patient-centered communication and shared decision making between patient and oncologist are vital to improve care and quality of life in patients with MBC. The Make Your Dialogue Count survey explored emotional needs of patients at initial diagnosis of MBC and treatment change to increase awareness about gaps and facilitate communication between patients and oncologists. The survey was conducted (June-August 2014) online, by telephone, or on paper among US women with MBC and US-licensed medical oncologists. Patient data were unweighted. Oncologist data were weighted by geographic region and years in practice by sex to match actual proportions in the population. Statistically significant differences between groups were determined by standard t-test of column proportions and means at the 95% confidence level. Between initial diagnosis of MBC and treatment change, some patients' attitudes and feelings adapted as their disease advanced. Fewer patients reported fear of the unknown (58% versus 44%) and distress over believing something could have been done to prevent disease progression (26% versus 12%), but more patients reported hope of keeping the disease stable (46% versus 59%) and confidence in treatment options (29% versus 37%). During their treatment journey, more women with children ≤17 years old were distressed because they believed something could have been done to prevent disease progression versus women with children 18+ years old or no children. There were instances of misalignment between patient expectations and what oncologists actually discussed with patients. Our findings suggest that patients exhibit an ability to adapt during their disease. Having a shared understanding of concerns and needs of patients serves to strengthen the patient-oncologist alliance and creates a framework for oncologists to tailor disease management and coping strategies to improve quality of life for patients of all ages with MBC.

Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer.

CONTEXT: Breast cancer estrogen-receptor (ER) status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy. OBJECTIVE: To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors. DESIGN, SETTING, AND PATIENTS: Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models. Randomized trials comparing (1): 3 regimens of cyclophosphamide, doxorubicin, and fluorouracil (January 1985 to April 1991); (2) 3 doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to April 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (September 1997 to March 1999). A total of 6644 node-positive breast cancer patients received adjuvant treatment. MAIN OUTCOME MEASURES: Disease-free and overall survival. RESULTS: For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%. CONCLUSION: Among patients with node-positive tumors, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50% in comparison with low-dose cyclophosphamide, doxorubicin, and fluorouracil as used in the first study.

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance).

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99-1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P < 0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P < 0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.

PURPOSE: Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. PATIENTS AND METHODS: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. RESULTS: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. CONCLUSION: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). PATIENTS AND METHODS: Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. RESULTS: Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days. CONCLUSION: Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.

Adipose concentrations of organochlorine compounds and breast cancer recurrence in Long Island, New York.

Several studies have measured the association between blood or adipose concentrations of organochlorinated compounds (OCs), such as pesticides and polychlorinated biphenyls (PCBs), and breast cancer. The estrogenic effects of OCs might adversely affect breast cancer recurrence. The participants were 224 women with nonmetastatic breast cancer enrolled in a New York-based case-control study. Supercritical fluid extraction followed by gas chromatography was conducted on adipose surgical specimens to determine OC concentrations. The mean follow-up time from surgery was 3.6 years. Thirty women (13.4%) were diagnosed with a recurrence. The concentration of pesticides and PCBs was correlated with baseline age and body mass index, but not with cancer stage. The highest tertile of total PCB concentration was associated with an increased risk of recurrence [relative risk (RR), 2.9; 95% confidence interval (CI), 1.02-8.2 versus the lowest tertile]. The risk for the highest tertile of the PCB congener Ballschmiter and Zell 118 was 4.0 (95% CI, 1.3-4.9). There was an increased risk for the middle level of the most abundant pesticide, 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene (RR, 2.3; 95% CI, 0.9-5.7), and for beta-hexachlorocyclohexane, but not for their highest levels. Self-reported home termiticide exposure, alcohol consumption (> or = 1 drink/day), and race were not associated with prognosis. The RR for current cigarette smoking at diagnosis was 2.1 (95% CI, 0.9-5.1). In contrast to previous data showing no relationship between OC exposure and risk of breast cancer in these women, adipose PCB concentrations were associated with tumor recurrence. Pesticide levels were not related to recurrence.

Lung cancer risk in white and black Americans.

PURPOSE: To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS: A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS: We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack-years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS: Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens.

Isolated sternal involvement in breast cancer: is it truly stage IV disease?

PURPOSE: There is no consensus regarding treatment for patients with breast cancer and isolated sternal involvement. Though classified as AJCC stage IV, this group of patients may have prolonged distant disease free survival. PATIENTS AND METHODS: Retrospective case series of 8 patients with isolated sternal recurrence. Information regarding age, menopausal status, hormonal receptor status, HER2 status, initial treatment, time to sternal recurrence, treatment of sternal involvement, and outcome was obtained. RESULTS: Median follow-up, 6 years. Seven of 8 diagnosed with metachronous sternal recurrence at a median of 3 years from initial breast cancer diagnosis, 1 with sternal involvement at initial diagnosis. Seven of 8 are alive, with one death from metastatic breast cancer 10 years after sternal recurrence. Six of 8 are without evidence of distant spread, 2 in continuous complete remission (CR) at 7 and 14 years from sternal recurrence. CONCLUSION: While a small cohort, the excellent survival of the group identifies this as a distinct subset of metastatic disease, requiring special treatment considerations. Isolated sternal involvement could represent direct local-regional extension rather than systemic spread.

Dose-Dense Chemotherapy: Principles, Clinical Results and Future Perspectives.

The dose intensity of adjuvant chemotherapy for breast cancer is an important predictor of clinical outcome. Dose-dense chemotherapy increases the dose intensity of the regimen by delivering standard-dose chemotherapy with shorter intervals between the treatment cycles. The rationale for dose-dense therapy stems from the Norton-Simon hypothesis: Sequential, consecutive dosing of chemotherapy using single or a combination of agents increases the dose density over alternating dosing, improving results. Supporting adjuvant studies, such as C9741, and the ensuing clinical experience indicate an improved disease-free and overall survival. Dosedense adjuvant chemotherapy improves clinical outcomes without increasing toxicity.

Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience.

PURPOSE: Older node-positive patients treated with newer adjuvant chemotherapy regimens have improvements in relapse-free and overall survival similar to younger patients. We compared toxicity of older and younger patients in three randomized trials of adjuvant chemotherapy. PATIENTS AND METHODS: Toxicity data were available for 93% of 6,642 patients enrolled. The three trials included: Cancer and Leukemia Group B (CALGB) 8541, a comparison of cyclophosphamide, doxorubicin, and fluorouracil in three dose schedules; CALGB 9344: cyclophosphamide and doxorubicin with or without paclitaxel; and CALGB 9741: cyclophosphamide, doxorubicin, and paclitaxel every 2 versus every 3 weeks. National Cancer Institute grade 3 to 5 toxicities were compared among age groups. RESULTS: Seven percent of patients (n = 458) were age 65 or older, 3% were 70 or older, 38% were 51 to 64, and 55% were 50 or younger. Twenty-four deaths (0.4%) were attributed to treatment; seven (1.5%) of 486 in patients 65 or older, 10 (0.40%) of 2,480 in patients who were 51 to 64 years, and seven (0.19%) of 3,676 occurred in patients younger than 50. In multivariate analysis, older patients were significantly more likely to have grade 4 hematologic toxicity, to have discontinued treatment for toxicity, or to have died of acute myeloid leukemia/myelodysplastic syndrome. There were no significant differences in grade 3 to 4 nonhematologic toxicity. CONCLUSION: Healthy older patients who met the strict eligibility criteria for these trials had a higher rate of hematologic toxicity and treatment-related deaths than younger patients, but no increase in nonhematologic toxicity. Elderly patients treated with newer adjuvant chemotherapy regimens derive the same benefits from newer chemotherapy regimens as younger patients but should be cautioned about the increased risk of toxicity and treatment-related death.

Dose density in adjuvant chemotherapy for breast cancer.

BACKGROUND: Dose-dense chemotherapy increases the dose intensity of the regimen by delivering standard-dose chemotherapy with shorter intervals between the cycles. This article discusses the rationale for dose-dense therapy and reviews the results with dose-dense adjuvant regimens in recent clinical trials in breast cancer. METHODS: The papers for this review covered evidence of a dose-response relation in cancer chemotherapy; the rationale for dose-intense (and specifically dose-dense) therapy; and clinical experience with dose-dense regimens in adjuvant chemotherapy for breast cancer, with particular attention to outcomes and toxicity. RESULTS: Evidence supports maintaining the dose intensity of adjuvant chemotherapy within the conventional dose range. Disease-free and overall survival with combination cyclophosphamide, methotrexate, and fluorouracil are significantly improved when patients receive within 85% of the planned dose. Moderate and high dose cyclophosphamide, doxorubicin, and fluorouracil within the standard range results in greater disease-free and overall survival than the low dose regimen. The sequential addition of paclitaxel after concurrent doxorubicin and cyclophosphamide also significantly improves survival. Disease-free and overall survival with dose-dense sequential or concurrent doxorubicin, cyclophosphamide, and paclitaxel with filgrastim (rhG-CSF; NEUPOGEN) support are significantly greater than with conventional schedules (q21d). CONCLUSIONS: The delivered dose intensity of adjuvant chemotherapy within the standard dose range is an important predictor of the clinical outcome. Prospective trials of high-dose chemotherapy have shown no improvement over standard regimens, and toxicity was greater. Dose-dense adjuvant chemotherapy improves the clinical outcomes with doxorubicin-containing regimens. Filgrastim support enables the delivery of dose-dense chemotherapy and reduces the risk of neutropenia and its complications.