Survival In Metastatic Breast Cancer Research Articles

Abstract P6-08-11: Regional variation in de novo metastatic breast cancer survival improvement over time using an institutional registry to support SEER analysis: 1990-2010

Abstract Background: It is not known how much de novo MBC (dnMBC) survival varies by where one lives and receives treatment in the US. Variation could exist depending on access to care, insurance availability, geographic area, and treatment options (urban vs. rural). Our objective is to measure variance in survival by Surveillance, Epidemiology, and End Results (SEER) region and compared to a non-academic institutional cohort. Methods: We compared change in disease specific survival (DSS) over time intervals1990-1998, 1999-2004 and 2005-2010, following diagnosis of first primary dnMBC among women in the SEER 9 population-based cancer registry using SEER 9 without Seattle-Puget Sound (S-PS) (n = 11,139) and Seattle Puget Sound separately (n = 1787). In a separate analysis we calculated and compared dnMBC DSS in our community-based cancer center registry located in the Seattle-Puget Sound region (n = 247) for the same time intervals. For the institutional cohort time to event used the outcome death from breast cancer confirmed from the patient chart or death certificate if information on cause of death was not available in the chart. For SEER data we used the SEERstat calculation for cause-specific survival as equivalent for disease specific survival (DSS). We estimated 5-year DSS cumulative incidence with 95% confidence intervals using the Kaplan-Meier method and compared survivor function equality by diagnosis years with log-rank tests. SEER*stat 8.3.4 was used for the SEER regional comparison and SPSS 24 for the institutional. Results: Patient age in the SEER registry population ranged from 18-93 years. The institutional cohort patient age range was 24-94 years. DSS improved over time for SEER 9 without Seattle-Puget Sound [1990-1998: 18.8% (95% CI: 17.6%, 20.0%);1999-2004; 22.0% (95% CI: 20.5%, 23.4%); 2005-2010: 24.6% (95% CI: 23.2%, 26.0%) (log-rank test=61.59, p<0.001)]. DSS for SEER Seattle-Puget Sound had a similar significant improvement gradient over time [1990-1998: 20.1% (95% CI: 17.1%, 23.2%)]; 1999-2004: 25.6% (95% CI: 21.9%, 29.4%); 2005-2010: 33.4% (95% CI: 29.7%, 37.1%) (log-rank test=42.46, p<0.001)]. DSS was significantly better in the Seattle-Puget Sound region in 2005-2010 (33.4%) compared to SEER9 without Seattle-Puget Sound (24.6%) (p=.017). Among dnMBC cases at the non-academic community cancer center, five year dnMBC DSS improved over time as well and by a larger margin [1990-1998: 28%, 95% CI: 18.2%, 37.8%; 1999-2004: 48%, 95% CI: 33.9%, 58.9%; 2005-2010: 55%, 95% CI: 45.3%, 64.5% (log rank test=9.65, p=.008)]. Conclusions: The SEER regional comparison indicates a significant regional survival difference for breast cancer patients with de novo stage IV metastatic breast cancer. Better survival in the Seattle-Puget Sound region is supported by the retrospective cohort analysis results from a center with a more detailed registry and complete follow up in the same region. Supplementation of regional survival SEER analysis with detailed analysis from an embedded institutions' dedicated registry could be used to enhance evaluation of factors such as standard of care that impact survival improvement. Citation Format: Malmgren JA, Calip GS, Atwood MK, Kaplan HG. Regional variation in de novo metastatic breast cancer survival improvement over time using an institutional registry to support SEER analysis: 1990-2010 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-11.

When do patient reported quality of life indicators become prognostic in breast cancer?

BackgroundVarious patient reported quality-of-life indicators are independently prognostic for survival in metastatic breast cancer and other cancers. The same measures recorded at first diagnosis of early breast cancer carry no corresponding prognostic information. The present study aims to assess at what time in the disease evolution the prognostic association appears.MethodsAmong 8024 patients enrolled in one of seven randomized controlled trials in early-stage breast cancer 3247 had a breast cancer relapse after a median follow-up of 12.1 years. Of these 677 had completed QL indicator assessments within defined windows 1, 2 or 3 months prior to relapse. We performed Cox regression analyses using these assessments and using identical instruments after relapse. All analyses were stratified by trial and adjusted for baseline clinicopathologic factors.ResultsQL indicators in the months before relapse were not significantly prognostic for subsequent survival with the possibly chance exception of mood at the second month before relapse. After relapse, physical well-being was statistically significantly associated with survival (P < 0.001). This prognostic significance increased in later post-relapse assessments. Similar findings were observed using patient-reported indicators for nausea and vomiting, appetite, coping effort, and health perception.ConclusionsBefore cancer relapse, QL indicators were not generally prognostic for subsequent survival. After relapse, QL indicators substantially predicted OS, with a stronger association later in the course of relapsed disease. Simple patient perception of disease burden seems unlikely to explain this sudden change: rather the patient’s awareness of disease relapse must contribute.

Score for the Survival Probability in Metastasis Breast Cancer: A Nomogram-Based Risk Assessment Model.

PurposeSurvival of metastatic breast cancer (MBC) patient remains unknown and varies greatly from person to person. Thus, we aimed to construct a nomogram to quantify the survival probability of patients with MBC.Materials and MethodsWe had included 793 MBC patients and calculated trends of case fatality rate by Kaplan-Meier method and joinpoint regression. Six hundred thirty-four patients with MBC between January 2004 and July 2011 and 159 patients with MBC between August 2011 and July 2013 were assigned to training cohort and internal validation cohort, respectively. We constructed the nomogram based on the results of univariable and multivariable Cox regression analyses in the training cohort and validated the nomogram in the validation cohort. Concordance index and calibration curves were used to assess the effectiveness of nomogram.ResultsCase fatality rate of MBC was increasing (annual percentage change [APC], 21.6; 95% confidence interval [CI], 1.0 to 46.3; p < 0.05) in the first 18 months and then decreased (APC, -4.5; 95% CI, -8.2 to -0.7; p < 0.05). Metastasis-free interval, age, metastasis location, and hormone receptor status were independent prognostic factors and were included in the nomogram, which had a concordance index of 0.69 in the training cohort and 0.67 in the validation cohort. Calibration curves indicated good consistency between the two cohorts at 1 and 3 years.ConclusionIn conclusion, the fatality risk of MBC was increasing and reached the summit between 13th and 18th month after the detection of MBC. We have developed and validated a nomogram to predict the 1- and 3-year survival probability in MBC.

Trastuzumab Emtansine: Antibody-drug Conjugate in Treatment of Human Epidermal Growth Factor Receptor-2-Positive Metastatic Breast Cancer

AbstractThe human epidermal growth factor receptor-2 (HER2)-targeted therapies have improved clinical outcomes for patients at any stage of HER2-positive breast cancer (BC). Trastuzumab, a monoclonal antibody that targets the HER2 receptor on BC cells, showed improved survival in metastatic BC (MBC). However, resistance to therapy arises in the majority of patients with advanced disease. Antibody–drug conjugate (ADC) is a relatively new development to deliver cytotoxic drugs specifically to cancer cells. Trastuzumab emtansine (T-DM1) is a HER2-targeted ADC, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent, emtansine (DM1, derivative of maytansine). T-DM1 has been approved for use in patients with MBC who have failed prior therapy with trastuzumab and a taxane. Dose finding Phase I study established the maximum tolerated dose at 3.6 mg/kg every 3 weeks. Phase I and II studies of T-DM1 have shown clinical activity and a favorable safety profile in HER2-positive MBC patients. The Phase III randomized EMILIA and TR3RESA trials demonstrated that T-DM1 significantly improves progression-free and overall survival in pretreated HER2-positive MBC patients. Nausea and fatigue are most commonly reported adverse drug reactions with T-DM1 and cardiac toxicity comparable with standard of care therapies. The drug is well tolerated in most patients, with a predictable pharmacokinetic profile and minimal systemic exposure to free cytotoxic DM1. T-DM1 has emerged as an effective therapeutic option for the management of patients with HER2-positive MBC.

Preliminary study on the role of serum PECAM-1 in metastatic breast cancer

Background: The metastatic breast cancer (MBC) is yet incurable with high mortality, thereby requiring improved biomarkers for predicting the outcome of palliative therapy in patients. The present study evaluated the correlation of serum platelet and endothelial cell adhesion molecule-1 (PECAM-1) with the prognosis of MBC patients. Methods: Thirty women initially diagnosed as MBC before any palliative treatment, were divided according to the median value of serum PECAM-1 level, Group A ( 4,058.89 pg/mL). After median 78 months follow-up from the preliminary surgery, 15 patients died of breast cancer. The Kaplan-Meier method and Cox regression analysis were used to determine progressionfree survival (PFS) and overall survival (OS) rates. Other data were analyzed by the chi-square test and t -test. Results: The 3-year survival of MBC patients in Group A was higher than Group B. More patients in Group B accepted the adjuvant endocrine therapy than Group A. The serum CA125 level was higher in Group A than Group B. The serum total cholesterol (TC), low-density lipoprotein (LDL), and fasting glucose were significantly higher in Group A than Group B patients (P=0.02, P 0.05). Conclusions: High serum level of PECAM-1 is related to a decline in 3-year survival of MBC. Whether serum PECAM-1 could predict the long-term survival of MBC necessitates additional clinical trials.

Effect of a mentor-based, supportive-expressive program, Be Resilient to Breast Cancer, on survival in metastatic breast cancer: a randomised, controlled intervention trial

Background:Because of medical advances, metastatic breast cancer (MBC) is now viewed as a chronic disease, rather than an imminent death sentence. Helping women live with this disease requires more than a medical approach to symptoms. Thus, a mentor-based and supportive-expressive program ‘Be Resilient to Breast Cancer’ (BRBC) was designed to help Chinese women with MBC enhance their resilience levels, biopsychosocial functions, and potentially extend their life span.Methods:A total of 226 women with MBC were randomly assigned, in a 1 : 1 ratio, to an intervention group (IG) that participated in BRBC or to a control group (CG) that received no intervention. Be Resilient to Breast Cancer was conducted for 120 min once a week. Primary outcomes were cancer-specific survival and secondary outcomes were resilience, Allostatic Load Index (ALI), anxiety, depression, and quality of life (QoL). The Cox proportional-hazards model was used for survival analysis and growth mixture models were performed for secondary outcomes.Results:Be Resilient to Breast Cancer did not significantly prolong 3- or 5-year survival (median survival, 36.7 months in IG and 31.5 months in CG). The hazard ratio for death was 0.736 (95% CI, 0.525–1.133, P=0.076; univariate Cox model) and 0.837 (95% CI, 0.578–1.211, P=0.345; multivariate Cox analysis). The IG improved in anxiety (ES=0.85, P<0.001), depression (ES=0.95, P<0.001), QoL (ES=0.55, P<0.001), resilience (ES=0.67, P<0.001), and ALI (ES=0.90, P<0.001) compared to CG.Conclusions:BRBC does not improve survival of women with MBC in this study, though longer follow up is warranted. It positively impacts resilience, QoL, ALI, and emotional distress.

270P - Untreated hormone receptor positive/HER2-negative metastatic breast cancer survival with front-line chemotherapy and maintenance endocrine therapy

270P - Untreated hormone receptor positive/HER2-negative metastatic breast cancer survival with front-line chemotherapy and maintenance endocrine therapy

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.

PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

Metastatic breast cancer: clinicopathological features and survival according to the site of metastasis

Study design: retrospective cohort study. Objectives: investigate clinical and pathological features, as well as the survival of metastatic breast cancer according to the site affected by the metastasis, osseous or extraosseous. Methods: the study population consisted of a cohort of 124 women with metastatic breast cancer assisted in an oncology referral hospital. The association between sociodemographic, tumoral and treatment variables and the site of metastasis was assessed with a chi-square test and the survival functions were estimated by the Kaplan-Meier method. Results: osseous-only metastasis was observed in 26.6% of patients and extra-osseous metastasis in 45.2%, the remainder presented metastasis in both sites. Among patients with osseous-only metastasis, 68.2% had been treated with hormonal therapy, compared with 44.9% of those with extraosseous metastasis (p=0.06); progesterone receptor–positive tumors were found in 63.6% and 43.3% of the patients in each group (osseous-only versus extraosseous), respectively (p=0.09). Overall 5-years survival rate was 38.5% (CI95%: 18.6-58.2) for patients with osseous-only metastasis and 24.8% (CI95%: 15.2-35.7) for patients with extraosseous metastasis. The mean survival time after the diagnosis of metastasis was 19.6 months in cases of bone-only metastasis and 12.1 in extraosseous metastasis. Conclusions: hormone receptor positivity and use of hormone therapy seem to be associated with the occurrence of isolated bone metastasis; patients within this group were suggested to have longer survival times.

Clinical Relevance of Serum HER2 and Circulating Tumor Cell Detection in Metastatic Breast Cancer Patients.

Presence of circulating tumor cells (CTCs) is associated with impaired survival in metastatic breast cancer (MBC). This study was designed to evaluate whether assessment of serum HER2 (sHER2) levels provide additional prognostic information in MBC. Two hundred and fifty-three MBC patients were enrolled in this multicentre trial. CTCs were detected before the start of first- or later-line treatment using the CellSearch system. sHER2 was determined using ELISA. ≥5 CTCs were detected in 122 of 245 evaluable patients (49.8%). One hundred and nineteen of 251 patients (47%) had sHER2 levels above 15 ng/ml. Median overall survival (OS) was 16.3 months in patients with elevated sHER2; median OS in patients with non-elevated sHER2 has not been reached (p=0.001). Patients with ≥5 CTCs were more likely to present with elevated sHER2 (61% vs. 33% in those with <5 CTC; p<0.001). In patients with HER2-negative tumors, elevated sHER2 was associated with shorter OS and PFS; in HER2-positive patients with OS only. Including sHER2, CTC status and established prognostic factors into a multivariate analysis, only the presence of CTCs and higher-line of therapy remained independent predictors of OS. Elevated levels of sHER2 are associated with worse survival, irrespective of the HER2 status of the tumor. However, sHER2 does not provide additional prognostic information in patients with known CTC status.

Spatial heterogeneity of MRI response to first-line hormonal therapy to predict progression-free survival in metastatic breast cancer.

e12544 Background: Whole-body magnetic resonance imaging (WB-MRI) can positively identify response to systemic therapy in metastatic breast cancer (MBC) by the analysis of water diffusivity, cellularity and cell variability. We adapted a novel methodology that captures patient-level, spatial response heterogeneity using the METastasis Response Assessment Diagnostic System (MET-RADS) using WB-MRI. This study evaluated whether spatial heterogeneity seen at the first response assessment is predictive of duration of treatment (i.e. progression-free survival, PFS) in patients on first line hormonal therapy for MBC. Methods: Patients on first line hormonal therapy for MBC had baseline and on-treatment response assessment WB-MRI scans. All patients had a primary breast mass in situ. Patients showing unequivocal disease progression at their first response assessment scans were excluded from further analysis. Criteria for response assessment utilised the methodology described by MET-RADS. A Likert five-point response assessment category (RAC) score (1 = response highly likely, 5 = progression highly likely) was applied to 14 anatomic regions (7 bone &amp; 7 soft tissue). Two scores reflecting the dominant and next most common response per region were recorded, capturing inter- and intra-region response heterogeneity. A novel Response Heterogeneity Index (RHI) summarised the response heterogeneity at the patient level. RHI and depth of response (mean RAC score for all involved regions) and therapy duration were analysed. Results: Twenty-one patients with primary breast mass in situ were analysed. Patients with higher levels of response heterogeneity (defined as RHI &gt; 5; n = 11) had significantly shorter PFS than those with RHI ≤5 (n = 10; median PFS: 11 vs 27 months; log rank test p = 0.011). The depth of response and PFS were unrelated (mean RAC ≤2.5 vs mean RAC &gt; 2.5; median PFS: 21 vs 18 months; log rank test p = 0.46). There were no correlations between RHI score and mean RAC (r2= 0.007). Conclusions: A low spatial heterogeneity of response is predictive of improved PFS in patients receiving first line hormonal therapy for MBC.

VEGFR2 cytoplasmic expression (VEGFR2ce) in relation to survival in metastatic breast cancer (MBC) patients (pts) treated with bevacizumab (Bev).

11523 Background: Bev is a monoclonal antibody that binds to VEGFA that demonstrated improved progression free survival (PFS) in MBC clinical trials. VEGFR2, NOTCH1, Integrin a1b2 and ILK are angiogenesis-related proteins possibly related with Bev efficacy. The correlation of these proteins expression and Bev survival variables was evaluated. Methods: We retrospectively analyzed 1st line chemotherapy in two HER2 negative MBC cohorts. Pts were treated between May-07 and July-14. Cohort 1 (C1) was treated with paclitaxel and Cohort 2 (C2) with paclitaxel and Bev. Expression of biomarkers was determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. Survival curves were calculated by Kaplan-Meier method and log-rank test. Cox model was used in multivariate analysis. Results: C1 had 42 pts. Median age was 63y. Tumor subtypes were divided in luminal (92.9%) and triple negative (TN) (7.1%). Visceral metastasis (mets) were present in 71.4%. Median follow-up (mFUP) time was 32.1m. mPFS was 8.0m and mOS was 33.5m. C2 had 29 pts. Median age was 57y. Luminal 79.3%; TN 20.7%; Visceral mets 79.3%; mFUP 38m. mPFS was 10.5m and mOS was 47m. In C2, high VEGFR2ce was correlated with improved PFS (high VEGFR2 16.5m x low VEGFR2 6.8m, p = 0.025). Breast cancer subtype, metastasis pattern and VEGFR2 expression were included in the multivariate analysis for PFS. VEGFR2 remained as independent factor (HR 0.35; IC95% 0.14 – 0.85, p = 0.021). In C1, VEGFR2 was not correlated with improved PFS (high VEGFR2 8.6m x low VEGFR2 8.0m, p = 0.24). Other markers were not associated with PFS. Conclusions: High VEGFR2ce was associated with increased PFS in patients treated with Bev. In MBC VEGFR2 may have a role as a predictive tool on benefit of antiangiogenic therapy.

Abstract P4-21-35: Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC)

Abstract Background: Pathologic complete response (pCR) to HER2-targeting neoadjuvant therapy (NT) predicts for improved survival (Cortazar et al, Lancet, 2014). The addition of pertuzumab to trastuzumab and docetaxel increased pCR rates, and, as first line treatment for MBC led to longer overall survival ([OS] Swain et al, NEJM 2015). Avoidance of anthracyclines in the adjuvant setting for HER2+ BC reduced the risk of secondary hematologic malignancies without a detriment to OS (Slamon et al, NEJM, 20111). Finally, nab-paclitaxel (nab) might provide an advantage over other taxanes via decreased use of steroids and may lead to increased response rates (RR). We designed a study of pertuzumab (pert), trastuzumab (trast), and nab, testing the feasibility and efficacy of this regimen in the LABC and metastatic breast cancer settings. Materials and Methods: Pts with Stages II-III LABC received six cycles of NT with pert (day 1 q 21 days), trast, and nab 100 mg/m2 (both given IV, weekly). Pts with untreated MBC received the same regimen until progression, toxicities, or patient or physician preference led to stopping therapy. Primary endpoints included pCR (LABC) and RR and progression-free survival (PFS) in MBC. Forty pts with LABC and 25 pts with MBC were to be accrued. The study was designed to test whether the pCR rate of Neosphere (Gianni et al, Lancet Oncol, 2012, &amp;gt; 45.8%) and the PFS rate of CLEOPATRA (median of &amp;gt; 18.5 months) can be matched or exceeded. Procurement of serial samples for assessment of tumor gene expression, circulating tumor cells, miRNA, and serum DNA profiling for exploratory biomarker analysis was carried out. Results:Twenty-two of 28 already enrolled pts with LABC (clinical stage II:15, stage III: 7) completed NT. The median age was 53 (34-77). The pCR rate was 86% (6/7) for hormone receptor negative (HR-) and 40% (6/15) for HR+ pts, with an overall pCR of 55%. Three pts without pCR following NT had residual BC with a HER2 negative phenotype. Eighteen of 22 pts required nab dose modifications. The most frequent toxicities following NT included elevated liver function tests:27%, peripheral neuropathy:23%, hematological toxicities:17%, diarrhea:18%, infusion reactions:18%. In the MBC cohort there were 13 of 16 enrolled pts with &amp;gt; 2 months of follow-up. The median age was 47 (31-65), 62% had HR+ disease. A CR rate of 4/13 (31%) and confirmed RR of 77% were observed. The median number of cycles with pert, trast, nab was 9 (3+ to 41); 11 of 13 pts required dose modifications or delays (3 of the delays were due to primary breast surgery performed upon response to treatment). At a median follow-up of 19 months, PFS and OS estimates are 63% (95% CI 0.09-0.93), and 89% (95% CI 0.61-1.0). Conclusion: The non-anthracycline-containing regimen of pertuzumab, trastuzumab, and nab-paclitaxel induced a high pCR rate in HER2+ BC. PFS is encouraging in MBC. Outcome of the fully accrued cohorts inclusive of residual cancer burden scores in the LABC cohort, and correlative data with exploratory biomarker analysis will be presented. Citation Format: Somlo G, Frankel P, Yeon C, Yuan Y, Yim J, Kruper L, Taylor L, Mortimer J, Waisman J, Jones V, Vito C, Paz B, Huria A, Li D, Gaal C, Tong T, Tumyan L. Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC) [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 P4-21-35.

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.

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

Retrospective Review for Prevalence and Survival in Metastatic Breast Cancer with Brain Metastasis in Two Patient Cohorts: One Collected 2000-2005 and the Second Collected 2006-2011

Purpose: To determine whether the new treatments for breast cancer CNS metastases improve survival by comparing the survival between two cohorts: 2000-2005 and 2006-2011. Patients and Methods: A retrospective, comparative, correlational chart review was performed. Data from 172 women diagnosed with CNS metastases between 2000 and 2011, was evaluated. Results: Approximately 10% of patients diagnosed with invasive breast cancer between 2000 and 2011 developed CNS metastases. The cohort was separated into four groups: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), HER2+ (ER -, PR-, HER2+) and TN (ER-, PR-, HER2-). There was a statistically significant difference in the overall survival between luminal A and luminal B (5.55 months vs. 15.3 months, respectively, p = 0.048). There was also a statistically significant difference in the overall survival between luminal B and TN (15.3 months vs. 7.49 months, respectively, p = 0.0181). There was no significant difference in overall survival between luminal B and HER2+ (15.3 months vs. and 10.98 months, respectively, p = 0.105), TN and HER2+ (7.49 months vs. 10.98 months, respectively, p = 0.514), and between luminal A and TN or HER2+ (5.55 months vs. 7.49 months, respectively, p = 0.428, or 5.55 months vs. 10.98 months, respectively, p = 0.491). Overall median survival of the patients in 2000-2005 and 2006-2011 were 6.64 months vs. 10.58 months, respectively (p = 0.0592). Conclusion: The results of our study showed that despite the new therapies there is little improvement in survival for brain metastasis in breast cancer.

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.

Improved survival in metastatic breast cancer 1985–2016

PurposeIn the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period. MethodsPatients consecutively diagnosed with disseminated breast cancer 1985–2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp. ResultsMedian survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change.Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%. ConclusionsSurvival in metastatic breast cancer improved 1985–2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset.

Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer.

While intact circulating tumor cells (iCTC) have independent negative prognostic impact on patients with metastatic breast cancer (MBC), the prognostic relevance of apoptotic CTC (aCTC) has not been validated in larger patient cohorts. This study assessed aCTC and iCTC statuses at baseline (CTCBL) and CTC kinetics (CTCKIN) as changes from CTCBL to one completed treatment cycle for their utility in predicting response, progression-free survival (PFS), and overall survival (OS) in MBC. Status of iCTC and aCTC was prospectively assessed in 442 patients using the CellSearch™ system. Different cutoffs were analyzed both for iCTC and aCTC (≥5, ≥10, ≥25 and ≥50 CTC/7.5ml). CTCKIN were characterized by ≥25% changes in CTC counts. Numbers of iCTC and aCTC at baseline correlated strongly (r=0.7). For iCTCBL positive patients, additional detection of aCTCBL had a significant prognostic impact on OS (aCTCBL positive 10.3 vs. aCTCBL negative 16.4months, p=0.012). Worst prognosis for OS was observed in patients with ≥50 iCTC/7.5ml and simultaneously detected aCTC. Determination of aCTCKIN showed stronger discriminating power than iCTCKIN, with higher PFS and OS for the group with decreasing CTCs (PFS 7.7 vs. 6.1; OS 22.2 vs. 16.4). Intact and aCTC are predictive of outcome in MBC. Apoptotic CTC counts ≥ 5/7.5ml in conjunction with iCTC at baseline have an independent unfavorable prognostic impact on OS. Decreasing aCTCKIN at ≥ 5/7.5ml in serial enumeration is associated with favorable outcome. Therefore, separate enumeration of iCTC and aCTC is useful in tailoring systemic treatment.

272P - Clinical and molecular analysis of long-term HER2 positive metastatic breast cancer survivors

272P - Clinical and molecular analysis of long-term HER2 positive metastatic breast cancer survivors