Prior Treatment Time Affects Survival Outcomes in Metastatic Breast Cancer

PURPOSE Sequential drug treatments in metastatic breast cancer (MBC) are disparate. Clinical trial data includes limited reporting of treatment context, primarily including the number of prior therapies. This study evaluates the relationship between prior treatment time, prior lines of treatment, and survival using a novel visualization technique coupled with statistical analyses. PATIENTS AND METHODS This retrospective cohort study used a nationwide, de-identified electronic health record–derived database to identify women with hormone receptor–positive, human epidermal growth factor receptor 2–negative MBC diagnosed in 2014 who subsequently received paclitaxel. Images were created, with individual patients represented on the y-axis and time, on the x-axis. Specific treatments were represented by colored bars, with Kaplan-Meier curves overlaying the image. Separate images assessed progression-free survival and overall survival (OS). Hazard ratios (HRs) and 95% CIs from Cox proportional hazards models evaluated the association between prior treatment time and OS. RESULTS Of 234 patients, median survival from first paclitaxel administration was 20 months (interquartile range, 8-53 months). An inverse relationship was observed between OS after paclitaxel and timing of administration. In adjusted models, each year on treatment prior to paclitaxel was associated with a 16% increased hazard of death after paclitaxel (HR, 1.16; 95% CI, 1.05 to 1.29). CONCLUSION OS after a specific treatment is dependent on when a drug is given in the disease context, highlighting the potential for an overall OS benefit to be observed on the basis of treatment timing. Prior time on treatment should be considered as a stratifying factor in randomized trials and a confounding factor when examining survival in observational data.

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Everolimus-Based Therapy versus Chemotherapy among Patients with HR+/HER2− Metastatic Breast Cancer: Comparative Effectiveness from a Chart Review Study

International Journal of Breast Cancer ◽

10.1155/2015/240750 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Nanxin Li ◽

Yanni Hao ◽

Jipan Xie ◽

Peggy L. Lin ◽

Valerie Koo ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Comparative Effectiveness ◽

Chart Review ◽

Proportional Hazards ◽

Metastatic Breast ◽

Retrospective Chart Review ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Cox Models

Objective. To compare the real-world effectiveness of everolimus-based therapy and chemotherapy in postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) metastatic breast cancer (mBC).Methods. This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2− mBC women in community-based oncology practices. Patients received everolimus-based therapy or chemotherapy for mBC between 07/01/2012 and 04/15/2013, after failure of a non-steroidal aromatase inhibitor. Overall survival (OS), progression-free survival (PFS), and time on treatment (TOT) were compared using Kaplan-Meier analysis and Cox proportional hazards models adjusting for line of therapy and baseline characteristics.Results. 234 and 137 patients received everolimus-based therapy and chemotherapy. Patients treated with everolimus-based therapy tended to have less aggressive mBC than patients treated with chemotherapy. Multivariate-adjusted Cox models showed that everolimus-based therapy was associated with significantly longer OS [hazard ratio (HR) = 0.37, 95% confidence interval (CI): 0.22–0.63], PFS (HR = 0.70, 95% CI = 0.50–0.97), and TOT (HR = 0.34, 95% CI: 0.25–0.45) than chemotherapy. Adjusted comparative effectiveness results were generally consistent across lines of therapy.Conclusion. In this retrospective chart review of postmenopausal HR+/HER2− mBC patients, treatment with everolimus-based therapy was associated with longer OS, PFS, and TOT than chemotherapy.

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Differences between taxanes in time on therapy and associated discontinuation events in metastatic breast cancer: Results from a U.S. claims analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.26_suppl.158 ◽

2013 ◽

Vol 31 (26_suppl) ◽

pp. 158-158 ◽

Cited By ~ 1

Author(s):

Rex W. Force ◽

Brooke A. Pugmire ◽

Gary Binder ◽

Cindy Duval ◽

Deya Corzo ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Median Time ◽

Proportional Hazards ◽

Metastatic Breast ◽

Cox Proportional Hazards ◽

Claims Analysis ◽

Insurance Plan ◽

Cox Proportional Hazards Models ◽

Clinical Benefits

158 Background: Taxanes in metastatic breast cancer (mBC) have demonstrated clinical benefits but have different toxicity profiles. This study evaluated differences in time to discontinuation (D/C) between taxanes overall and by specific events associated with D/C (i.e., death, adverse events (AE), subsequent therapy). Methods: Women receiving >1 dose of either paclitaxel (P), docetaxel (D), or nab-paclitaxel (nab-P) between 2006-2009 were identified by ICD-9 codes indicative of mBC from a commercial payer claims database. Logistic regression and Cox-proportional hazards models were used to compare rates of D/C and time to D/C, respectively. Control variables were age, use of prior or concurrent chemo, and comorbidity score. Drug D/C was defined as no taxane administration for 35 days. AE within 35-days after D/C were considered taxane-associated. Death or disenrollment from the insurance plan within 90 days and initiation of subsequent therapy within 60 days after D/C were considered temporally associated with D/C. Results: 4,503 pts with mBC were included (2,599 received D; 1,643 received P, and 261 received nab-P). The most common reason for D/C in all pts was AEs (37.8%), initiation of subsequent therapy (34.4%), and death or disenrollment (8.4%). A higher proportion of pts on D (29.4%) and P (17.5%) had D/C due to neutropenia vs nab-P (6.9%, p<0.001 for both comparisons). A higher proportion of pts on nab-P (12.3%) continued on therapy until death/disenrollment vs D (8.9%, p 0.046) or P (7.1%, p 0.023). Similarly, a higher proportion of pts on nab-P (51.2%) initiated subsequent therapy at D/C of taxane vs D (31%) or P (37.3%; p<0.01 for both comparisons). Median time to D/C was 85 days for each of D and P, and 127 days for nab-P (p<0.05). Median time to D/C associated with AEs, neutropenia, death/disenrollment or subsequent therapy were significantly longer for nab-P compared with D or P (p<0.05). Conclusions: Women treated for mBC stayed on nab-P therapy 50% longer than with other taxanes. This time on therapy advantage also indicated that pts on nab-P were less likely to D/C due to AEs, more likely to stay on therapy, and more likely to be candidates for subsequent therapies.

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Measuring on-treatment genome-wide tumor copy number alterations in cell-free DNA (cfDNA) in plasma is highly prognostic in metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1097 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1097-1097

Author(s):

Adriana Aguilar ◽

Josiane Lafleur ◽

Susie Brousse ◽

Cristiano Ferrario ◽

Graham McLennan ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Copy Number ◽

Tumor Response ◽

Treatment Time ◽

Metastatic Breast ◽

Progression Free Survival ◽

Copy Number Alterations ◽

Genome Wide ◽

Metastatic Setting

1097 Background: The clinical management of metastatic breast cancer depends on the measurement of tumor response to successive drugs by serial imaging and changes in blood tumor markers, which remain the standard of care despite poor sensitivity and specificity. Highly sensitive and specific cfDNA secreted from the tumor can detect the changes in tumor-specific aberrations that have been shown to be associated with patient response in the metastatic setting. However, most approaches require prior sequencing of the tumor to target specific known mutations. Methods: Using low coverage genomic sequencing, a genomic instability number (GIN) was measured in cfDNA based on the detection of genome-wide tumor-specific DNA copy number alterations for 27 patients with metastatic breast cancer. The GIN value and its variation from baseline before treatment, as well as within 10 days and 3 weeks after start of therapy were compared with tumor response, progression free survival (PFS) and overall survival (OS) of the patients. Patients were followed for a median of 22 months and we used a previously published GIN threshold at 170 for high vs low GIN values. Sequencing was performed blinded to the clinical results. Results: Baseline GIN values were not associated with tumor response at 3or 6 months, but showed a trend towards lower OS with higher GIN (p = 0.12). GIN values fell by an average of 28% in responders (stable disease or response) and 23% in those with progression (p = 0.85), but remained lower at 3 weeks only in the responders. High GIN values within 10 days and 3 weeks were associated with markedly worse OS (p = 0.014 and p = 0.009 respectively) and those at 3 weeks with worse PFS (p = 0.017). Hence the median survival of patients with high GIN at 10 days or 3 weeks was 12 months vs not reached for those with low GIN. The percentage drop of GIN at 10 days but not at 3 weeks was significantly associated with PFS (p = 0.016). Conclusions: These results demonstrate that GIN values of cfDNA measured at early on-treatment time points can predict PFS and OS with a high degree of accuracy. These findings deserve further study in a larger cohort but hold the promise of early prediction of clinical outcomes in a tumor-independent genome-wide approach.

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A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.9.1377 ◽

1988 ◽

Vol 6 (9) ◽

pp. 1377-1387 ◽

Cited By ~ 240

Author(s):

I F Tannock ◽

N F Boyd ◽

G DeBoer ◽

C Erlichman ◽

S Fine ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Metastatic Breast ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Rank Test ◽

Primary Surgery ◽

Dose Levels

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

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Prognosis of Women With Metastatic Breast Cancer by HER2 Status and Trastuzumab Treatment: An Institutional-Based Review

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.9844 ◽

2010 ◽

Vol 28 (1) ◽

pp. 92-98 ◽

Cited By ~ 463

Author(s):

Shaheenah Dawood ◽

Kristine Broglio ◽

Aman U. Buzdar ◽

Gabriel N. Hortobagyi ◽

Sharon H. Giordano

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Proportional Hazards ◽

Metastatic Breast ◽

Cox Proportional Hazards ◽

Rank Test ◽

Her2 Status ◽

First Line ◽

Risk Of Death ◽

Trastuzumab Treatment

Purpose The purpose of this study was to determine whether trastuzumab improves prognosis of women with metastatic human epidermal growth factor receptor 2 (HER2)/neu –positive breast cancer beyond that of women with HER2/neu-negative disease. Patients and Methods Two thousand ninety-one women with metastatic breast cancer diagnosed from 1991 to 2007, with known HER2/neu status and who had not received trastuzumab in the adjuvant setting, were identified. Disease was classified into the following three groups: HER2/neu negative, HER2/neu positive without first-line trastuzumab treatment, and HER2/neu positive with first-line trastuzumab treatment. Overall survival (OS) was estimated using the Kaplan-Meier product-limit method and compared between groups with the log-rank test. Cox proportional hazards models were used to determine associations between OS and HER2/neu status after controlling for patient characteristics. Results One hundred eighteen patients (5.6%) had HER2/neu-positive disease without trastuzumab treatment, 191 (9.1%) had HER2/neu-positive disease and received trastuzumab treatment, and 1,782 (85.3%) had HER2/neu-negative disease. Median-follow-up was 16.9 months. One-year survival rates among patients with HER2/neu-negative disease, HER2/neu-positive disease and trastuzumab treatment, and HER2/neu-positive disease and no trastuzumab treatment were 75.1% (95% CI, 72.9% to 77.2%), 86.6% (95% CI, 80.8% to 90.8%), and 70.2% (95% CI, 60.3% to 78.1%), respectively. In a multivariable model, women with HER2/neu-positive disease who received trastuzumab had a 44% reduction in the risk of death compared with women with HER2/neu-negative disease (hazard ratio [HR] = 0.56; 95% CI, 0.45 to 0.69; P < .0001). This HR varied with time and was significant for the first 24 months and not significant after 24 months. Conclusion Our results show that women with HER2/neu-positive disease who received trastuzumab had improved prognosis compared with women with HER2/neu-negative disease.

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Metastatic breast cancer incidence, site and survival in Australia, 2001–2016: a population-based health record linkage study protocol

BMJ Open ◽

10.1136/bmjopen-2018-026414 ◽

2019 ◽

Vol 9 (2) ◽

pp. e026414

Author(s):

Sarah J Lord ◽

Belinda E Kiely ◽

Sallie-Anne Pearson ◽

Benjamin Daniels ◽

Dianne L O’Connell ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Disease ◽

Distant Metastasis ◽

Systemic Therapy ◽

Proportional Hazards ◽

Breast Cancer Incidence ◽

Metastatic Breast ◽

Population Based ◽

Cox Proportional Hazards

IntroductionAdvances in systemic therapy for early and metastatic breast cancer (BC) over the last two decades have improved patients’ survival, but their impact on metastatic disease outcomes at a population level is not well described. The aim of this study is to investigate changes in the incidence, site and survival of metastatic disease for women with a first diagnosis of BC in 2001–2002 vs 2006–2007.Methods and analysisPopulation-based retrospective cohort study of women with first primary invasive BC registered in the New South Wales (NSW) Cancer Registry in 2001–2002 and 2006–2007. We will use linked records from NSW hospitals, dispensed medicines, outpatient services and death registrations to determine: women’s demographic and tumour characteristics; treatments received; time to first distant metastasis; site of first metastasis and survival. We will use the Kaplan-Meier method to estimate cumulative incidence of distant metastasis, distant recurrence-free interval and postmetastasis survival by extent of disease at initial diagnosis, site of metastasis and treatment-defined tumour receptor type (hormone receptor-positive, human epidermal growth factor receptor-2-positive, triple negative). We will use Cox proportional hazards regression to estimate the relative effects of prognostic factors, and we will compare systemic therapy patterns by area-of-residence and area-level socioeconomic status to examine equity of access to healthcare.Ethics and disseminationResearch ethics committee approval was granted by the Australian Institute of Health and Welfare (#EO2017/2/255), NSW Population and Health Services (#HREC/17/CIPHS/19) and University of Notre Dame Australia (#0 17 144S). We will disseminate research findings to oncology, BC consumer and epidemiology audiences through national and international conference presentations, lay summaries to BC consumer groups and publications in international peer-reviewed oncology and cancer epidemiology journals.

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Which benefit from subsequent chemotherapy lines beyond the second for women with metastatic breast cancer? Evidence from a single-center retrospective analysis of survivorship.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.255 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 255-255

Author(s):

G. Bernardo ◽

R. Palumbo ◽

A. Bernardo ◽

C. Teragni ◽

F. Sottotetti ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Retrospective Analysis ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Univariate Analysis ◽

Metastatic Breast ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Hazards Model

255 Background: Although the true impact of chemotherapy (CT) in metastatic breast cancer (MBC) is still debated, in the routine clinical practice an increasing number of women asking for further treatment after progression receive subsequent CT lines. This study aimed to assess which benefit could be brought by the succession of CT lines in patients treated for MBC and to identify women who benefit from these treatments. Methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a 7-year period (May 1999-July 2006). With overall survival (OS) data updated at December 1, 2008, the median follow-up was 125 months (range 48-192), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS. Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months (980 patients, 1st line, range 4-208) to 22.6 months (838 patients, 2nd line), 14.6 months (684 patients, 3rd line), 12.4 months (302 patients, 4th line), 9.4 months (88 patients, 5th line), 8.2 months (45 patients, seven or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the 3rd line (median 5.2 months, range 4.8-6.2). In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments (p<0.001). Conclusions: CT beyond the 2nd line may be beneficial in a significant subset of women treated for MBC, with improved TTF and OS. These findings could help physician in planning an appropriate strategy of subsequent schedules for women with symptomatic MBC who responded to their 1st line CT, while non responder patients should be considered for clinical trials.

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Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer

Future Oncology ◽

10.2217/fon-2020-0604 ◽

2020 ◽

Vol 16 (33) ◽

pp. 2763-2778

Author(s):

Miguel Martin ◽

Jose A Garcia-Saenz ◽

Luis Manso ◽

Antonio Llombart ◽

Alejo Cassinello ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Endocrine Therapy ◽

Objective Response ◽

Metastatic Breast ◽

Clinical Trial Data ◽

Progression Free Survival ◽

Standard Of Care ◽

First Line ◽

Free Survival

The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.

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