Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine

O’Shaughnessy, Joyce; Koeppen, Hartmut; Xiao, Yuanyuan; Lackner, Mark R.; Paul, Devchand; Stokoe, Christopher; Pippen, John; Krekow, Lea; Holmes, Frankie A.; Vukelja, Svetislava J.; Lindquist, Deborah; Sedlacek, Scot; Rivera, Ragene; Brooks, Robert J.; McIntyre, Kristi; Brownstein, Carrie; Hoersch, Silke; Blum, Joanne L.; Jones, Stephen E.

doi:10.1158/1078-0432.ccr-15-0636

Cited by 54 publications

(87 citation statements)

References 30 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20 Given the low number of events overall (13%), we pooled the control and experimental arms to test the relationship of PAM50 intrinsic subtypes with prognosis for patients receiving adjuvant chemotherapy, and observed results consistent with those previously reported (Figure 2a). Of note, only ~30% of the HER2 + patients received adjuvant trastuzumab following chemotherapy when adjuvant trastuzumab became available, which likely explains the poor prognosis of the HER2-enriched subtype.…”

Section: Resultssupporting

confidence: 75%

“…As the addition of capecitabine to adjuvant therapy showed no statistical benefit across IHC subtypes, 20 we evaluated whether there was any differential benefit from capecitabine within the PAM50 intrinsic subtypes. As shown in Figure 2c, no differences were seen within the HER2-enriched, luminal A or luminal B subtypes with the addition of capecitabine versus not.…”

Section: Resultsmentioning

confidence: 99%

“…After a median follow-up of 6.4 years, 346 disease-free survival (DFS) events were observed and no improvement in DFS was observed (hazard ratio (HR), 0.84; 95% confidence interval, 0.68 to 1.04; P =0.1136). 20 Little is known about the molecular landscape in a clinically defined high-risk population, therefore we aimed to define the impact of tumor heterogeneity on therapeutic benefit and overall prognosis in this patient population. We molecularly profiled 861 patients’ primary breast cancers using an 800-gene expression panel, a 35-gene copy-number alteration (CNA) panel and a PIK3CA mutation assay.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population

Wilson¹,

Yu²,

Lu³

et al. 2016

npj Breast Cancer

Self Cite

View full text Add to dashboard Cite

Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. We sought to characterize the molecular landscape of high-risk breast cancer patients enrolled onto an adjuvant chemotherapy study to understand how disease subsets and tumor immune status impact survival. DNA and RNA were extracted from 861 breast cancer samples from patients enrolled onto the United States Oncology trial 01062. Samples were characterized using multiplex gene expression, copy number, and qPCR mutation assays. HR+ patients with a PIK3CA mutant tumor had a favorable disease-free survival (DFS; HR 0.66, P=0.05), however, the prognostic effect was specific to luminal A patients (Luminal A: HR 0.67, P=0.1; Luminal B: HR 1.01, P=0.98). Molecular subtyping of triple-negative breast cancers (TNBCs) suggested that the mesenchymal subtype had the worst DFS, whereas the immunomodulatory subtype had the best DFS. Profiling of immunologic genes revealed that TNBC tumors (n=280) displaying an activated T-cell signature had a longer DFS following adjuvant chemotherapy (HR 0.59, P=0.04), while a distinct set of immune genes was associated with DFS in HR+ cancers. Utilizing a discovery approach, we identified genes associated with a high risk of recurrence in HR+ patients, which were validated in an independent data set. Molecular classification based on PAM50 and TNBC subtyping stratified clinical high-risk patients into distinct prognostic subsets. Patients with high expression of immune-related genes showed superior DFS in both HR+ and TNBC. These results may inform patient management and drug development in early breast cancer.

show abstract

Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population

Wilson¹,

Yu²,

Lu³

et al. 2016

npj Breast Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…23 Furthermore, the addition of gemcitabine also did not improve outcomes in the NSABP B-38 study when added to adjuvant chemotherapy. 24 In the Japanese CREATE-X trial, adjuvant capecitabine alone did improve DFS and OS in patients with HER2 negative disease who did not achieve a pCR after neoadjuvant anthracycline and taxane therapy, with the Triple Negative Breast Cancer-Review of Current and Emerging Therapeutic Strategies most impressive benefit being for patients with TNBC.…”

Section: Role Of Additional Agentsmentioning

confidence: 96%

Triple Negative Breast Cancer—Review of Current and Emerging Therapeutic Strategies

Ballinger

Kremer

Miller

2016

Oncology &Amp; Hematology Review (US)

View full text Add to dashboard Cite

T riple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of 'triple negative' is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies. KeywordsTriple negative, breast cancer, therapeutics 1 It is more common in African American women, younger women, and those with a germline BRCA1 mutation. Due to lack of ER, PR, and HER2 and the significant heterogeneity among TNBC, no approved targeted therapies exist and standard treatment remains cytotoxic chemotherapy. While response rates to chemotherapy in early stage disease are high, patients remain at high risk for relapse and prognosis remains inferior to other types of breast cancer. Subtyping and molecular characteristicsIn a seminal paper by Perou et al., gene expression profiling was used to categorize breast cancers into five molecular subtypes. The basal-like type is characterized by lack of ER, PR, and HER2 expression, expression of cytokeratins and EGFR, and a clinically more aggressive phenotype.2 This subtype overlaps with TNBC but the terms are not synonymous; in fact, about one fourth of TNBCs are not basal-like by gene expression, and some non-TNBCs are basal-like by molecular profiling (see Figure 1). 3,4 As more is discovered about the biology of TNBC, it has become clear that this category of breast cancer is not one homogeneous tumor type, but rather is made up of a group of molecularly diverse tumor subtypes. These subtypes have varying gene expression profiles, clinical characteristics, and responses to treatment. In an effort to translate the heterogeneity of TNBC into rational clinical design, Lehmann and colleagues further characterized TNBC into six distinct subtypes based on molecular profiles, each with unique drivers and clinical phenotypes. These subtypes include basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor(LAR).5 Each exhibited different sensitivities to therapeutic agents, both in cell line models and in some retrospective clinical trials...

show abstract

“…7 Of 2611 women, 1304 were randomly assigned to receive AC-T and 1307 to receive AC-XT. This study failed to meet its primary end point, DFS, [HR 0.84; 95% confidence interval (CI) 0.67–1.05; p = 0.125]; however, a statistically significant improvement in OS, a secondary end point, was seen with AC-XT vs. AC-T (HR 0.68; 95% CI 0.51–0.92; p = 0.011).…”

Section: Review and Analysis Of The Datamentioning

confidence: 99%

CREATE-X a role for capecitabine in early-stage breast cancer: an analysis of available data

Zujewski

Rubinstein

2017

npj Breast Cancer

View full text Add to dashboard Cite

Breast cancer patients with residual disease after neoadjuvant chemotherapy and surgery may benefit from additional anti-cancer therapies. Capecitabine, an oral antimetabolite and prodrug of 5-Flurouracil, has been approved for treating metastatic breast cancer. One randomized clinical trial (CREATE-X) of capecitabine versus no additional therapy has been conducted in women with early stage breast cancer who received standard chemotherapy pre-operative therapy and had residual invasive breast cancer at the time of surgery. Results from CREATE-X, showed that capecitabine had a statistically significant survival advantage compared with no additional therapy. This perspective provides a review and analysis of the available data from CREATEx in the context of results from other adjuvant trials of capecitabine in early stage breast cancer that had disease–free survival as a primary endpoint. We conclude that although the previously published studies of capecitabine in the adjuvant setting did not meet their primary endpoint, the data from these studies are consistent with the hypothesis that capecitabine may offer additional survival benefit in patients with chemo-refractory breast cancer at the time of surgery after receiving standard chemotherapy. In these patients, offering a course of adjuvant capecitabine or enrolling the patient in a clinical trial are appropriate therapeutic options. The patient should be informed about both the increased survival observed in the CREATEx trial and the expected toxicities from capecitabine chemotherapy.

show abstract

Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine

Cited by 54 publications

References 30 publications

The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population

The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population

Triple Negative Breast Cancer—Review of Current and Emerging Therapeutic Strategies

CREATE-X a role for capecitabine in early-stage breast cancer: an analysis of available data

Contact Info

Product

Resources

About