Overall Survival In Metastatic Breast Cancer Research Articles

Effects of socioeconomic status and race on survival and treatment in metastatic breast cancer.

Race and socioeconomic factors affect outcomes in breast cancer. We aimed to assess the effect of race and neighborhood socioeconomic status (SES) on overall survival and treatment patterns in patients with metastatic breast cancer (MBC). This is a retrospective cohort study involving patients (N = 1246) with distant breast cancer metastases diagnosed at UPMC Magee Women's Breast Cancer Clinic from 2000-2017. Overall survival and treatment patterns were compared between races (Blacks and whites) and SES groups (defined using Area Deprivation Index). Low SES, but not tumor characteristics, was associated with Black race (P < 0.001) in the study population. Low SES (Median [Interquartile Range, IQR] survival 2.3[2.2-2.5] years vs high SES 2.7[2.5-3.1] years, P = 0.01) and Black race (Median [IQR] survival 1.8[1.3-2.3] years, vs white 2.5[2.3-2.7] years P = 0.008) separately were associated with worse overall survival in patients with MBC. In the Cox Proportional Hazard model with SES, race, age, subtype, number of metastases, visceral metastasis, and year of diagnosis as covariates, low SES (Hazard ratio 1.19[1.04-1.35], P = 0.01), but not Black race (Hazard ratio 1.19[0.96-1.49], P = 0.12), independently predicted overall survival in MBC. Moreover, patients from low SES neighborhoods and Black race received fewer lines of chemotherapy than high SES and whites. In conclusion, low neighborhood SES is associated with worse outcomes in patients with MBC. Poor outcomes in Black patients with MBC, at least in part is driven by socioeconomic factors. Future studies should delineate the interplay between neighborhood SES, race, and their effects on tumor biology in MBC.

Abstract P4-01-34: Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect

Abstract Background: In metastatic breast cancer (MBC), the benefits of progression-free survival (PFS) and overall survival (OS) is not always proportional. This dissociation is related to the multiple other treatment options such as chemotherapy after disease progression and these treatments would contribute to the long post-progression survival. A constant improvement of PFS that translates into OS has been reported in anti-HER2 antibody containing treatments. In the era of antibody drug conjugates (ADC), we aim to examine the relationship between the increments of PFS and OS in MBC. Methods: We have used “ metastatic breast cancer” and “antibody drug conjugate” to search for clinical trials that report both PFS and OS. Hazard ratios (HR) and median survival were analyzed. Increments in PFS (delta PFS) and increments in OS (delta OS) were compared between studies. Results: A total of 5 trials were identified and summarized in table 1. The target of ADC is HER2 (N=4) or Trop2 (N=1). In DESTINY-Breast 03 trial, the control arm is another ADC (T-DM1). The control arms in all the other 4 trials are chemotherapy. The HR of PFS ranged from 0.28 to 0.65 and the HR of OS ranged from 0.48 to 0.68. The HR of PFS is smaller than HR of OS in all of the 5 trials. The median OS was not reached in 1 of the trials (DB-03) and was thus removed from the analysis for delta PFS and delta OS. In the comparison of delta PFS, the increments of median PFS fell between 2.9 and 4.8 months. The increments of median OS were between 5.4 and 6.6 months. All the delta OS are larger than the delta PFS in the four trials.Conclusion: Regardless of the antibody drug targets, ADC provides consistent improvements in median OS that surpasses the improvements in median PFS in metastatic breast cancer. The mechanism warrants further investigation. Citation Format: I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu. Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-34.

Abstract CT144: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer

Abstract Pre-clinical and clinical data suggest that the bone marrow (BM) environment provides breast cancer (BC) cells a protective haven against chemotherapeutic insult, endocrine therapies, and immune recognition. Novel agents that intercept cross-talk between BC cells and the host could therefore improve the depth of response to therapies and potentially increase overall survival in metastatic BC. We have previously shown that bone metastatic BC cells reside in perivascular niches expressing high levels of SDF-1α (CXCL12) and E-selectin, two molecules for which emerging data have demonstrated a significant role in metastatic BC progression. Our prior pre-clinical studies have shown that E-selectin inhibition specifically prevents circulating BC cells from homing to the BM, whereas CXCR4 blockade mobilizes micrometastases from the marrow into circulation, where they may be sensitized to chemotherapeutic cell kill. Given the normal role of these molecules in host immune responses, E-selectin/CXCR4 blockade has additional potential to impact the tumor immune microenvironment. GMI-1359 is a small molecule, glycomimetic compound with dual inhibitory activity against E-selectin and CXCR4. We hypothesize that GMI-1359 can block E-selectin and CXCR4 binding to E-selectin ligands and SDF-1, disrupting the protective effects of the bone microenvironment on tumor cells. A single-center, phase 1b, open-label, single and multiple ascending dose study (NCT04197999) is therefore evaluating GMI-1359 in patients with HR+ metastatic breast cancer with bony metastases who are stable or minimally progressive on endocrine therapy, with or without a CDK4/6 inhibitor. To date, 2 patients have been enrolled and received single monthly doses of 3.5, 5.0 and 7.0 mg/kg followed by 3 daily doses of 7 mg/kg. Both patients have completed treatment with no dose limiting toxicities observed. Coincident with GMI-1359 administration at all dose levels, we observed mobilization of CD34+ cells coupled with a reduction in elevated serum sE-selectin levels, demonstrating the dual functionality of the compound. Initial peripheral blood immunophenotype data on one patient revealed a redistribution of myeloid derived suppressor cells and a shift in macrophage polarization from M2 to M1. Notably, we observed similar immune alterations in ongoing preclinical studies in the E0771 syngeneic BC mouse model. We found that orthotopically-engrafted mice treated with single agent 1359 had a significant increase in the ratio of CD8/Tregulatory cells isolated from the primary tumor and BM. We also observed a decrease in primary tumor M-MDSCs and lung metastasis-associated macrophages. In summary, our preliminary clinical data suggest that GMI-1359 is well-tolerated and elicits on-target effects expected from disruption of the host microenvironment. Ongoing clinical and preclinical work will define the efficacy of this strategy to enhance responses to chemo and immune therapies. Citation Format: P. Kelly Marcom, Trevor T. Price, Andrew S. Murray, William E. Fogler, John L. Magnani, Helen Thackray, Eric Feldman, Dorothy Sipkins. Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT144.

Abstract P1-18-13: Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer

Abstract Background: HER2 targeted therapies, such as trastuzumab, pertuzumab and trastuzumab-emtansine (TDM-1), have improved survival of patients (pts) with HER2+ metastatic breast cancer (MBC). In the pivotal phase III study of pertuzumab/trastuzumab/docetaxel in MBC (NCT00567190), only 10% of pts received prior trastuzumab, whereas in modern practice the majority of recurrent HER2+ MBC pts have received neo(adjuvant) trastuzumab [NAT]. Survival outcomes in the real world setting have not been well described. Methods: Pts were part of a prospective national registry collecting clinicopathologic, treatment and outcome data for HER2+ MBC pts diagnosed between 10/2006 and 1/2019. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. A multivariable analysis was used to assess the impact of prior trastuzumab-use on survival. Analysis was stratified by estrogen receptor (ER) status to exclude the impact of concurrent endocrine therapy in the ER positive (ER+) subgroup. The TABITHA registry is sponsored by BioGrid Australia with financial support from Roche Products Pty Limited. Results: Of 254 HER2+ MBC pts in the registry, 225 received HER2 directed therapy in the first-line advanced disease setting and were included for analysis. Median age was 58 years, 100 (44%) had de novo metastatic disease, 131 (58%) had ER+ disease and 24 (11%) had brain metastases. Of the 125 (56%) pts with recurrent disease, 89 (71%) pts received NAT. First-line HER2 therapy was pertuzumab plus trastuzumab in 176 (78%), trastuzumab in 38 (17%), TDM-1 in 9 (4%), and lapatinib or pertuzumab alone in single pts (&amp;lt;1%). Concurrent chemotherapy was given in 205 (91%) pts, all but one case was taxane-based. The response rate to anti-HER2 therapy among all MBC pts evaluable for response was 42% in pts who received NAT, and 53% in pts who did not (p=0.20). Median progression free survival (PFS) was 16.4 months and 22.6 months, in pts who were trastuzumab-treated and trastuzumab-naïve, respectively (HR 1.44 [95%CI 0.99 - 2.10], p=0.05). The median overall survival (OS) from first-line HER2-directed therapy for MBC was 41.2 months in pts who had prior NAT, and 52.0 months in trastuzumab-naïve pts (HR 1.73 [95%CI 1.04 - 2.86], p=0.03). On multivariable analysis, prior trastuzumab-exposure was no longer significantly associated with survival. Factors significantly associated with PFS were ER status (HR 0.63, p=0.02) and age (HR 1.02, p=0.04), while only age was significantly associated with OS (see table). Among the subset of 93 ER negative (ER-) pts, prior NAT was significantly associated with inferior PFS (HR 1.97 [95%CI 1.11 - 3.52], p=0.02) and OS (HR 2.13 [95% CI 1.00 - 4.57], p=0.046). Multivariable analysis found only age and presence of brain metastases to be significantly associated with OS in the ER- subgroup. NAT exposure did not impact on PFS (HR 1.15, [95% CI 0.70 - 1.90], p=0.58) or OS (HR 1.37, [95% CI 0.68 - 2.73], p=0.37) in ER+ pts. Conclusions: In pts with HER2+ MBC, receipt of NAT was associated with inferior survival when HER2 targeted therapy was used in the metastatic setting on univariate analysis, but this finding was not seen in a multivariable analysis. Furthermore, the impact of NAT was only observed in the subset of pts with ER- tumors, raising the possibility that the disease-course in ER+ subgroup is not entirely HER2 driven. Survival rates of these HER2+ MBC pts treated in the community are comparable to that reported in clinical trials. Cox proportional hazard models for OS in MBC on HER2-targeted therapyUnivariableMultivariableHR95% CIPHR95% CIPAdjuvant trastuzumab Y vs N1.731.04 – 2.850.031.370.64 – 2.940.42De novo metastatic disease Y vs N0.610.37 – 1.020.060.810.38 – 1.730.59Estrogen receptor positive vs negative0.880.53 – 1.440.600.690.41 – 1.180.18Brain metastases Y vs N1.800.88 – 3.670.111.960.90 – 4.260.09Age (years)1.021.00 – 1.040.051.031.01 – 1.060.003 Citation Format: Yada Kanjanapan, Dan Tran, Sheau Wen Lok, Peter Gibbs, Richard De Boer, Belinda Yeo, Sally Greenberg, Frances Barnett, Louise Knott, Gary Richardson, Rachel Wong, Michelle Nottage, Ian Collins, Javier Torres, Janine Lombard, Julie Johns, Michael Harold, Laeeq Malik. Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-13.

Prognostic values of cell free DNA, CA 15.3, and ESR1 circulating mutations variations in hormone receptor (HR)-positive metastatic breast cancer (MBC) patients under aromatase inhibitor (AI).

e12534 Background: Circulating cell free DNA (cfDNA), CA 15.3 and circulating tumor DNA (ctDNA) have been associated with survival in MBC. These 3 biomarkers have never been compared. Methods: We retrospectively included all patients treated in our center between 2010 and 2012 for a HR+ MBC, who had clinical progression during the first line of aromatase inhibitor (AI) and available plasma samples. CfDNA level (ng/mL), CA 15.3 level (U/mL) and ESR1 circulating mutation level (Y537N, Y537S, Y537C and D538G, identified by ddPCR) were determined at time of clinical progression (Tp) and 3 months before (Tp-3). Biomarkers values at Tp and Tp-3 as well as their variations were analyzed according to clinical progression and overall survival (OS). Results: 91 patients were analyzed. CA 15.3 was elevated ( &gt; 30 U/mL) in 71/91 (78%) at Tp and 62/91 (68%) at Tp-3. Higher CA 15.3 was associated with worse OS, especially at Tp (HR = 1.0006/unit at both times, p = 0.009 at Tp; p = 0.08 at Tp-3). Higher cfDNA was associated with worse OS, both at Tp and Tp-3 (HR = 1.006/unit, p &lt; 0.0001 and HR = 1.007/unit, p = 0.02, respectively). An ESR1 mutation was detected in 14/91 at Tp-3 (15%) and 28/91 at Tp (31%). ESR1 mutation detection was strongly correlated with OS both at Tp and Tp-3 (HR = 2.4, p = 0.0005 and HR = 1.97, p = 0.03, respectively). Between Tp-3 and Tp, overall median CA 15.3 and ESR1 mutation level increased (p &lt; 0.0001 and p = 0.007, respectively) and were related to poorer OS (HR = 1.007/unit, p = 0.0002 and HR = 3.1, p = 0.05). In contrast, CfDNA was not correlated at all with clinical progression (36/91 increase, 36/91 decrease, and 19/91 stable cfDNA). ROC curve analysis identified a 59% CA 15.3 increase as the best cut-off for predicting progression, but with poor performance (AUC = 0.64). Multivariate analysis showed that CA 15.3 at Tp (HR = 1.0006/unit, p = 0.006), cfDNA at Tp (HR = 1.005/unit, p = 0.01), ESR1 detection at Tp (HR = 2.7, p = 0.0002) and CA 15.3 increase between Tp-3 and Tp (HR = 1.006/unit, p = 0.003) were associated with poor OS. Conclusions: All 3 biomarkers are correlated with OS in MBC treated with AI. CfDNA variation is poorly related to clinical progression while CA 15.3 variation or ESR1 mutation detection are much more reliable. Overall the better performance is observed with ESR1 mutation detection.

Abstract P1-14-06: Long-term treatment patterns and OS in metastatic breast cancer by intrinsic subtypes in a clinical setting in Sweden

Abstract Background Breast cancer is the most common female cancer in Sweden, and patients diagnosed with early stage have a good curative prognosis. However, once metastases are detected, the disease is incurable. There is lack of detailed knowledge on the current management of metastatic breast cancer (MBC), especially treatment lines beyond second or third line. The aim was to describe long-term treatment sequences and OS for metastatic breast cancer patients by intrinsic subtypes in a clinical setting in Sweden. Method In this observational cohort study, women with MBC treated between 2009-2017 were identified in the RealQ® clinical database (Uppsala University Hospital, Sweden). Clinical characteristics, complete MBC treatment regimens, and overall survival (OS) were obtained. Patients were classified into intrinsic subtypes as determined by gene expression profiling i.e., luminal A, luminal B, HER2 subtype, and basal-like (also called triple negative breast cancer [TNBC]). OS was defined from date of first metastatic diagnosis until date of death, migration or end of study. Survival rates were estimated using the Kaplan-Meier method. Subgroup analyses among deceased patients were conducted for all treatment lines and combinations. Treatment exposure rates for each treatment category were calculated using the following formula: exposure rate = person-years for the treatment category/total person-years × 100. Results The full analysis set comprised 371 MBC patients (mean age 67 years, 88% with performance status 0 or 1) of which 350 patients could be subtyped: 118 (34%) Luminal A, 119 (34%) Luminal B, 68 (19%) HER2, and 45 (13%) TNBC. Median follow-up was 27 months and median OS was 32.5 months; 5-year survival rates for Luminal A,Luminal B,HER2, and TNBC were 27%, 29%, 36%, and 7%, respectively. In total 245 patients died during the observation period. The deceased patients had been treated with mean 4.5 lines (median 4, range 1-18), mean time from last treatment to death was 5.4 weeks (median 0, range 0-224). Luminal B patients (n=79) were younger (mean age 66.4 vs. 70.7 years), had more often 2+ metastatic sites (64.6% vs. 57.8%) and visceral as primary metastatic location (69.6% vs. 60.2%) compared with Luminal A patients (n=83). Generally, Luminal B patients were treated with chemotherapy more frequently than Luminal A patients, and chemotherapy was more often at later treatment lines. Total exposure rate for all chemotherapy were 33.6% among Luminal B patients vs. 24.1% among Luminal A patients (p=0.03), and for all endocrine therapy 49.4% among Luminal B patients vs. 61.9% among Luminal A patients (p=0.02). There was no difference in mortality for Luminal B and A patients when adjusting for age, number of metastatic sites, visceral metastatic location, and treatment (p&amp;gt;0.05). Conclusion This observational study of MBC patients in clinical practice shows relatively short OS despite an extensive management with numerous treatment lines and combination therapies. Regardless of differences in treatment patterns for Luminal A and B patients the long-term OS was similar for these patient groups, highlighting the importance of awareness and careful consideration in management of MBC beyond second or third treatment line. Citation Format: Lindman H, Sjöberg F, Wiklund F, Christensen HN. Long-term treatment patterns and OS in metastatic breast cancer by intrinsic subtypes in a clinical setting in Sweden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-06.

The Value of Progression-Free Survival in Metastatic Breast Cancer: Results From a Survey of Patients and Providers.

Background. Value assessments and treatment decision making typically focus on clinical endpoints, especially overall survival (OS). However, OS data are not always available, and surrogate markers may also have some value to patients. This study sought to estimate preferences for progression-free survival (PFS) relative to OS in metastatic breast cancer (mBC) among a diverse set of stakeholders—patients, oncologists, and oncology nurses—and estimate the value patients and providers place on other attributes of treatment. Methods. Utilizing a combined conjoint analysis and discrete choice experiment approach, we conducted an online prospective survey of mBC patients and oncology care providers who treat mBC patients across the United States. Results. A total of 299 mBC patients, 100 oncologists, and 99 oncology nurses completed the survey. Virtually all patients preferred health state sequences with contiguous periods of PFS, compared with approximately 85% and 75% of nurses and oncologists, respectively. On average, longer OS was significantly (P < 0.01) preferred by the majority (75%) patients, but only 15% of nurses preferred longer OS, and OS did not significantly affect oncologists’ preferred health state. However, in the context of a treatment decision, whether a treatment offered continuous periods of stable disease holding OS constant significantly affected nurses’ treatment choices. Patients and providers alike valued reductions in adverse event risk and evidence from high-quality randomized controlled clinical trials. Conclusions. The strong preference for observed PFS suggests more research is warranted to better understand the reasons for PFS having positive value to patients. The results also suggest a range of endpoints in clinical trials may have importance to patients.

Association between circulating tumor cells and peripheral blood monocytes in metastatic breast cancer

Background:We retrospectively evaluated the correlation between a baseline measurement of circulating tumor cells (CTCs) and inflammation-based scores in patients with metastatic breast cancer (MBC).Methods:The optimal value of inflammation-based scores as the neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) to predict survival was determined and compared with CTC <5 or ⩾5 per 7.5 ml of blood.Results:In the overall population of 516 women with MBC, CTCs correlated with peripheral blood monocytes (p = 0.008) and neutrophils (p = 0.038). In triple-negative tumors, CTCs correlated with monocyte count (p = 0.009); in HER2+ tumors, CTCs correlated with neutrophil count (p = 0.009), with a trend versus monocyte count (p = 0.061), whereas no correlation was found in HER2– estrogen receptor-positive (ER+) tumors. In multivariate analysis only monocytes were associated with ⩾5 CTCs (OR = 2.72, 95% CI 1.09–6.80, p = 0.033). In multivariable analysis for predictors of overall survival, CTC (⩾5 versus <5), number of metastatic sites (>1 versus 1), tumor subtypes (triple-negative versus HER2– ER+ tumors) and MLR only remained significant.Conclusions:CTC and MLR are predictors of overall survival in MBC. CTC correlates with monocytes, in particular in triple-negative tumors.

Abstract P2-16-01: Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy

Abstract Background: While metastatic breast cancer (MBC) is considered an incurable disease, nearly one-fifth of patients live longer than five years following diagnosis. In an effort to identify novel agents earlier, surrogate end points of overall survival (OS) such as response or progression are often employed in randomized controlled trials (RCTs). The goal of this analysis is to evaluate patterns of outcome reporting and the relationship of OS with surrogate measures in RCTs of patients with MBC. Methods: The analysis was based on data from a systematic review of patients with MBC evaluating the clinical impact of chemotherapy intensity on survival. Reports of phase 2-3 RCTs published between 1990-2013 comparing more intense chemotherapy regimens (higher dose intensity or use of additional agents) with less intense were identified. For each RCT, clinical, treatment, demographic and outcome data were extracted. Outcomes evaluated included OS, progression free survival (PFS), and time to progression (TTP) with a focus on median survival and hazard ratios (HRs) as measures of treatment effect. Survival post progression (SPP) was calculated as the difference between median survival and median progression free time. The relations between various outcome measures were estimated utilizing weighted Pearson correlation coefficient (CORR) adjusted by Fisher's transformation. Weights were assigned proportionally to the sample size of individual RCTs. Results: The review identified 70 eligible RCTs including 15,043 patients with MBC. Average median OS, PFS, and TTP were 19.2, 6.9, and 8.1 months reported in 96%, 60%, and 43% of studies, respectively. Progression could be determined in 66 studies, while 6 RCTs provided both outcomes. TTP was more often utilized in earlier studies (65% in 1990-2000, 35% in 2001-2008, and 33% in 2009-2013) and it was superseded by PFS in later years (20%, 70% and 81%, respectively). Only 37%, 33%, and 11% of RCTs reported HRs for OS, PFS, and TTP, respectively. HRs were more often available in recent publications (20% in 1990-2000, 22% in 2001-2008, 63% in 2009-2013 provided HR for OS). The correlation between reported HR and HR estimated by the ratio of arm-specific median survival times was high for OS (CORR=0.87, 95%CI: 0.73-0.94) and TTP (CORR=0.92, 95%CI: 0.61-0.99) and slightly lower for PFS (CORR=0.72, 95%CI: 0.44-0.87). The relationship between OS and surrogate measures (PFS, TTP) was weaker. The correlation between HR for OS and PFS was 0.49 (95%CI: 0.21-0.69) and for OS and TTP it was 0.26 (95%CI: -0.13-0.58). Survival time following progression was dependent on treatment type and was longer in less intense arms than more intense (mean SPP: 12.4 months vs. 11.4 months, P=0.0155). Conclusions: In RCTs of patients with MBC treated with chemotherapy, when HR is not reported and if necessary statistical conditions are met, the HR approximated by ratio of median survival times may be a suitable proxy estimate. In agreement with other reports, neither PFS nor TTP are acceptable surrogate outcomes for OS in MBC, as survival following progression may be substantial. In these patients, crossover and post-trial treatments may influence the relationship between OS and surrogate measures. Citation Format: Culakova E, Poniewierski MS, Crawford J, Dale DC, Lyman GH. Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-16-01.

The effect of androgen receptor expression on clinical characterization of metastatic breast cancer.

In breast cancer (BC), androgen receptor (AR) expression is related to estrogen receptor (ER) and/or progesterone receptor (PgR) expression. AR expression is an indicator of good prognosis in breast cancer regardless of hormone receptor (HR) status. In this study, we evaluated the effect of AR-related gene expression on clinical characterization of metastatic BC. We performed RNA-Seq to evaluate gene expression using mRNA extracted from 37 patients with metastatic BC. Intrinsic subtype prediction, analysis of differential gene expression, and gene set enrichment pathway analysis were then performed. Metastatic BCs were categorized into three subgroups based on AR, ER, PgR, and HER2 expression. According to this subcategorization, 70 genes including AR, ER, and HER2 were differentially expressed among the three groups. In gene set enrichment pathway analysis, the low AR group was associated with the cell cycle pathway, whereas mammalian target of rapamycin (mTOR) pathways was prevalent in the high ER and AR group. In survival analysis, a higher level of AR expression correlated with prolonged overall survival in metastatic BC (high expression vs. low expression, median OS 53.1 vs. 27.2 months, p=.001). In conclusion, we propose that AR and AR-related gene expression could be utilized to predict the prognosis of metastatic BC and thus may be useful in treatment planning for refractory BC.

Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis.

Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e., model R (2)) of the variability between the PFS-OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R (2) increased to 55%. However, the HRPFS-HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended.

Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic breast cancer.

Although improved long-term prognoses for patients with metastatic breast cancer (MBC) have been demonstrated, few reports address overall survival (OS) with sufficient follow-up. Furthermore, the relevance of immunohistological subtypes to OS in MBC has not been clarified. We evaluated, retrospectively, the OS of patients who had been initiated on systemic therapy for MBC between 2000 and 2008. The subjects of this study were 527 patients with MBC treated by systemic therapy. The median survival time (MST) was 55.5months. The MST for each immunohistological subtype was as follows: luminal, 59.9months; luminal-HER2, not reached; triple-negative, 18.6months; and HER2-enriched, 49.9months. According to multivariate analysis, metastasis-free intervals of ≥2years and treatment with anthracycline for MBC were predictive of better OS. The predictors of shorter OS included disease progression after first-line treatment for MBC, triple-negative, and all histological factors, except papillotubular carcinoma, with liver metastasis, and having three or more initial metastatic sites. The prognosis of the patients with MBC in this series was better than that reported before 2000, which is probably attributable to the use of novel, improved pharmacological agents. For example, luminal-HER2 tumors can be treated using both aromatase inhibitors and trastuzumab. Because of the lower toxicities, it is now possible to administer these agents for longer periods, resulting in better prognoses.

Abstract P6-08-40: Survival of metastatic hormone receptor (HR) positive/HER2 negative; HER2+; and triple negative (TN) breast cancer based on initial presentation

Abstract Introduction: Median overall survival (OS) for patients (pts) with metastatic breast cancer (MBC) is described as 2-3 years, but few reports compare OS for de novo versus relapsed disease. The recognized clinical subtypes of breast cancer (HR positive[+] /HER2 negative; HER2+; TN) are known to have variable OS clinically, but this has not been systematically documented. We hypothesized that pts relapsing from a non MBC stage (relapsed) might have different OS than those presenting initially with metastases (de novo), and that OS would differ for the three clinical biomarker subgroups. Methods: Using the Breast Cancer Outcomes Unit database, we identified all women diagnosed with MBC, de novo or relapsed, in British Columbia between 01/2001 and 12/2009 and referred to the BC Cancer Agency. Review of medical records confirmed ER, PR and HER2 status. Survival from MBC diagnosis was calculated for relapsed vs de novo in the three biomarker subgroups. Results: After excluding pts with a synchronous or prior contralateral disease, we identified 3645 women with known ER. Median follow up was 91 months. HER2 known (n=3010) and unknown (n=635, 17%) cases had the same median OS (17 months [m]) and HR status (72% ER+). Trastuzumab (T) was standard in MBC during this era, but fewer than 10% had adjuvant T (introduced mid 2005) which explains the high number of HER2+ MBC cases. We previously reported longer OS for HER2+ disease relapsing after adjuvant therapy without T (older cohort) than after adjuvant T (SABCS 2013 Lohrisch). HER2 unknown pts were excluded from further survival analyses. Three percent of cases with known PR were ER negative/PR +. Therefore ER was used as the main determinant of HR status. For the entire cohort and all biomarker groups, OS was longer for denovo than for relapsed MBC. Overall Survival - relapsed vs de novo MBC for each biomarker subtype Relapsed MBCDe novo MBC SubgroupsN dead/totalMedian OS, mN dead/totalMedian OS, mP-valueAll cases with known ER2124/231115593/69926&amp;lt;.0001HR+/ HER2 negAll821/91224290/36434&amp;lt;.0001PR known414/47720251/31934&amp;lt;.0001PR unknown407/4352839/45330.1315TNBCAll368/3919110/126150.0001HER2+All935/100811193/209170.0061ER neg268/278758/609.50.2191ER+667/73015135/149250.0088 OS was longest for denovo HR+/HER2 negative (34m) and shortest for HER2+/ER negative (7m) and TN (9m) relapsers. The difference in OS for relapsed vs denovo HER2+ disease was significant for HR+ but not HR negative cases, likely due to small numbers in the latter subset. Conclusion: Relapsers experience shorter OS than their denovo biomarker counterparts, possibly due to the selective pressure of adjuvant therapy on disease biology. When restricted to pts who received systemic therapy for MBC, OS figures may be higher. Novel therapies may decrease the total number of relapsers, and improve OS in MBC for all, but are unlikely to narrow the OS gap between relapsed and denovo groups. Trials exploring therapies for MBC of all biomarker types should therefore stratify by stage at initial diagnosis. Citation Format: Wendie-Lou D den Brok, Caroline Speers, Gondara Lovedeep, Emily Baxter, Scott Tyldesley, Lohrisch Caroline. Survival of metastatic hormone receptor (HR) positive/HER2 negative; HER2+; and triple negative (TN) breast cancer based on initial presentation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-40.

Relationship between OS and PFS in metastatic breast cancer (MBC): Review of FDA submission data.

1035 Background: An improvement in overall survival (OS) in a randomized controlled study is the gold standard endpoint for the regular approval of new treatments in MBC. Progression-free survival (PFS) has been used for approval of second and third-line indications or accelerated approval of first-line indications. We have further explored the relationship between OS and PFS in MBC. Methods: We reviewed 12 randomized clinical trials in 8,431 patients with MBC. The trials led to new drug approvals or were presented at an ODAC meeting. All of these trials had PFS as a primary or secondary endpoint. Due to important limitations (e.g., lack of endpoint definitions, inconsistent PFS definitions, or insufficient information on trial statistical design) with some published trials, we limited our evaluation and endpoints correlation to data reviewed by the FDA. The relationship between PFS and OS in MBC was investigated using a weighted linear regression model, where each trial was weighted by the sample size. T...

Combination or sequential single agent for the treatment of metastatic breast cancer (MBC) patients (pts). Impact of further chemotherapy (CT) in overall survival (OS) in the Alamo registry.

Abstract Abstract #2121 Introduction: Combinations can improve OS in MBC; however sequential single agent is sometimes preferred. In a recent report, pts receiving paclitaxel monotherapy in first line had a significantly worse OS if they were not receiving post study CT (PSC); no difference was seen in pts receiving paclitaxel+gemcitabine (Llombart, EBCC 2008). In this trial only 58% of pts received PSC.&amp;#x2028; Purpose: To assess, outside the context of a clinical trial, the amount of MBC pts receiving CT beyond first line, as well as the impact of combination use and further CT lines in their OS.&amp;#x2028; Methods: Alamo 1-2 is a breast cancer patient registry run by the GEICAM. 15482 pts diagnosed from 1990-1997 in 54 sites were included in the database. 4668 pts were stage IV; 778 (16.7%) metastatic at diagnosis and 3890 (83.3%) have had a recurrence.&amp;#x2028; Results: 3045 (65%) pts received CT in first line, 83% were combinations (with anthracyclines 42%, CMF 16%, taxane+anthracyclines 9.4% or +other agents 8%) and 16% were monotherapy. Among other variables studied, only previous treatment (in early stage) was influencing the choice of a combination (pts without previous CT received more combinations than pts receiving CMF, than pts receiving anthracyclines). Median survival for pts receiving single agent was significantly shorter compared to pts receiving combination, 16.2 and 21.85 months (m) respectively, HR=1.37 (IC 95%: 1.21-1.55; p&amp;lt;0.0001). Several covariates showed significant prognostic value in survival in the Cox multivariate model: monotherapy treatment in first line, anthracyclines pre-exposure, age &amp;gt; 65, negative hormonal receptor status, hepatic disease, Grade 3 and ≥ 3 disease sites. Half of the pts never received further CT after first line treatment. Only age and number of disease sites were influencing this decision in the Cox multivariate model. Median survival was 24.9 m in pts receiving further CT and 14.5 m in the ones not receiving it. In pts not receiving further CT, median OS was significantly shorter if they were treated with single agent in first line in comparison to those receiving previous combination: HR= 1.59 (IC 95%: 1.33-1.89; p&amp;lt; 0,00001). This difference was not significant in pts receiving further CT: HR= 1.15 (IC 95%: 0.97-1.37; p=0.101).&amp;#x2028; Conclusion: Our data show that only half of the MBC pts receive further CT after first line; they have longer survival. We found significant evidence that further CT is impacting the OS in pts treated with single agent in first line, but not in those receiving previous combination. Those facts should be taken into consideration when selecting single agent or a combination in first line. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2121.

Concordance of study objectives with efficacy findings in metastatic breast cancer (MBC) treatment trials

6600 Background: Despite ongoing development of new agents, overall survival in MBC remains discouraging. We reviewed large randomized controlled trials (RCTs) published since 2000 to compare stated objectives with efficacy endpoints. Methods: Systematic review of RCTs of systemic antineoplastic treatment in advanced / metastatic breast cancer, published 2000–2006 in English. Studies enrolling fewer than 100 patients or performed only at sites outside North America and Europe were excluded. Study success was characterized with regard to the primary endpoint as described in prospective power calculations. Results: 68 RCTs, enrolling 24,956 patients, met inclusion criteria. The 68 RCTs comprised 83 efficacy comparisons due to multiple arms and/or more than one primary endpoint. Frequency of success was similar by geographic location and presence of industry sponsorship, but higher for noninferiority comparisons ( Table 1 ). 5 of 13 non-inferiority studies reported unplanned superiority findings for the experimental arm, while 11 of 39 studies failing to meet planned superiority endpoints made statements regarding equivalence or superiority to control treatments. For 10 of 20 successful superiority studies, reported results did not match/exceed planned between-group differences, though the comparisons reached statistical significance: 4 such studies substantially exceeded planned enrollment (2 of which recalculated sample size after reviewing interim data), while reasons for attaining superiority in 6 cases were unclear. Of the remaining 10 superiority comparisons, 4 reached significance due to underperforming control arms (enabling PFS/TTP differences of &lt;2 months to establish superiority), 2 exceeded point estimates, and 4 exceeded estimated between- group ratios. Conclusions: Slippage from prospective study goals, even in large randomized trials, may contribute to a disconnect between the profusion of research activity and disappointing efficacy gains in MBC. No significant financial relationships to disclose. [Table: see text]

Epirubicin/paclitaxel (EP) vs. capecitabine/paclitaxel (XP) in first-line metastatic breast cancer (MBC): A prospective, randomized multicentre phase III study of the AGO breast cancer study group

517 Background: Anthracyline-taxane combinations have the highest response rates in high risk MBC. Recently, anthracyclines and taxanes have become standards for adjuvant breast cancer chemotherapy. The addition of capecitabine to docetaxel improved overall survival in MBC. This regime was associated with a high rate of side effects (actually FN was not different from Taxotere mono - it was more the addition of cape AEs to Taxotere AEs). Earlier phase II studies with XP are able to show efficacy with better tolerability including less febrile neutropenia. Methods: Our aim was to show non-inferiority of XP to EP. The primary endpoint was progression-free survival (PFS). Secondary endpoints were toxicity and overall survival (OS).Patients (pts) were treated with 6x E 60 mg/m2 and P 175 mg/m2 d1 q21d, or with 6× X 2×1000 mg/m2 d1–14 q 21d and P 175 mg/m2 d1 q21d. Results: During a period of 2.5 y the planned 340 pts (170 in each arm) in 63 centres were recruited. The median number of cycles was 6 in both arms. The median PFS for EP was 11.8 months, and 12.3 for XP (p=ns). OS also was not different between the arms. The response rate (RECIST) was 41.0% (CR 6.6%, PR 34.4%) for EP and 41.5% (CR 8.5%, PR 33.1%) for XP. The main toxicity was myelosuppression (10% of cycles grade 3/4). Febrile neutropenia was seen in 5 cases in EP and in 1 case in XP. Skin toxicity grade 3 was observed in 5 of XP pts. Two patients stopped treatment for cardiological reasons in EP, and 4 patients for GI reasons in XP. Conclusions: This first analysis shows a comparable efficacy of the non-anthracycline regimen XP to the EP combination in first-line MBC. The toxicity is relatively low compared to other non-anthracycline containing combination therapies. XP is therefore an appropriate option for pts with anthracycline pretreated first line MBC. [Table: see text]