Distant Breast Research Articles

Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer

Distant breast cancer metastases are nowadays routinely biopsied to reassess receptor status and to isolate DNA for sequencing of druggable targets. Bone metastases are the most frequent subgroup. Decalcification procedures may negatively affect antigenicity and DNA quality. We therefore evaluated the effect of several decalcification procedures on receptor status and DNA/RNA quality. In 23 prospectively collected breast tumors, we compared ERα, PR and HER2 status by immunohistochemistry in (non-decalcified) tissue routinely processed for diagnostic purposes and in parallel tissue decalcified in Christensen's buffer with and without microwave, EDTA and Formical-4. Furthermore, HER2 fluorescence in situ hybridization and DNA/RNA quantity and quality were assessed. We found that the percentage of ERα-positive cells were on average lower in EDTA (P=0.049) and Formical-4 (P=0.047) treated cases, compared with controls, and PR expression showed decreased antigenicity after Christensen's buffer treatment (P=0.041). Overall, a good concordance (weighted kappa) was seen for ERα, PR and HER2 immunohistochemistry when comparing the non-decalcified control tissues with the decalcified tissues. For two patients (9%), there was a potential influence on therapeutic decision making with regard to hormonal therapy or HER2-targeted therapy. HER2 fluorescence in situ hybridization interpretation was seriously hampered by Christensen's buffer and Formical-4, and DNA/RNA quantity and quality were decreased after all four decalcification procedures. Validation on paired primary breast tumor specimens and EDTA-treated bone metastases showed that immunohistochemistry and fluorescence in situ hybridization were well assessable and DNA and RNA yield and quality were sufficient. With this, we conclude that common decalcification procedures have only a modest negative influence on hormone and HER2 receptor immunohistochemistry in breast cancer. However, they may seriously affect DNA/RNA-based diagnostic procedures. Overall, EDTA-based decalcification is therefore to be preferred as it best allows fluorescence in situ hybridization and DNA/RNA isolation.

The Benefit of Baseline Staging-Risk Assessment of Distant Breast Cancer Metastases by Tumor Stage.

Despite recommendations of international societies, use of baseline staging in breast cancer varies considerably. We retrospectively analyzed the prevalence of metastases in each pTN stage to estimate the benefit of staging. The prevalence of metastases at primary diagnosis (M1) and in the first year after diagnosis (M112) was determined in 2,906 patients. The prevalence of M1 was 0.95% [95% confidence interval (CI)=0.53-1.70%] in pT1pN0, 2.17% (95% CI=1.00-4.64) in pT1pN1 and 1.53% (95% CI=0.78-2.99%) in pT2pN0. The prevalence of M112 was 2.17% (95% CI=1.47-3.18%) in pT1pN0 and 3.25% in pathological stage IIA (upper confidence bound 5.14%). In pT2pN1 the prevalence of M1 and M112 was 3.49% (95% CI=1.96-6.14%) and 6.35% (95% CI=4.15-9.60%), respectively. Results for stage pT3pN0 and higher were inconclusive. Baseline staging can be safely abandoned in pathological stage I and IIA. Individual decisions should be made for pT2pN1. Staging is recommended in stages of pT3pN0 or higher.

Utility of Clinical Breast Examinations in Detecting Local-Regional Breast Events After Breast-Conservation in Women with a Personal History of High-Risk Breast Cancer.

Although breast cancer follow-up guidelines emphasize the importance of clinical examinations, prior studies suggest a small fraction of local-regional events occurring after breast conservation are detected by examination alone. Our objective was to examine how local-regional events are detected in a contemporary, national cohort of high-risk breast cancer survivors. A stage-stratified sample of stage II/III breast cancer patients diagnosed in 2006-2007 (n=11,099) were identified from 1217 facilities within the National Cancer Data Base. Additional data on local-regional and distant breast events, method of event detection, imaging received, and mortality were collected. We further limited the cohort to patients with breast conservation (n=4854). Summary statistics describe local-regional event rates and detection method. Local-regional events were detected in 5.5% (n=265) of patients. Eighty-three percent were ipsilateral or contralateral in-breast events, and 17% occurred within ipsilateral lymph nodes. Forty-eight percent of local-regional events were detected on asymptomatic breast imaging, 29% by patients, and 10% on clinical examination. Overall, 0.5% of the 4854 patients had a local-regional event detected on examination. Examinations detected a higher proportion of lymph node events (8/45) compared with in-breast events (18/220). No factors were associated with method of event detection. Clinical examinations, as an adjunct to screening mammography, have a modest effect on local-regional event detection. This contradicts current belief that examinations are a critical adjunct to mammographic screening. These findings can help to streamline follow-up care, potentially improving follow-up efficiency and quality.

Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer: TEXT and SOFT Trials.

Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease. The TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk. SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments. Premenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.

Abstract A82: Medicaid disenrollment in Tennessee and disparities in stage at diagnosis and surgery for female breast cancer

Abstract Purpose: To assess the effects of Medicaid disenrollment on stage at diagnosis and delay in surgery for female breast cancer among nonelderly women. Background: Although Medicaid expansions have received considerable attention in the literature, Medicaid contractions have received much less attention. Tennessee's Medicaid program experienced a dramatic Medicaid contraction when the program disenrolled approximately 170,000 nonelderly adults after implementing a new benefit policy in 2005. Despite the fact that this was the largest disenrollment in the history of Medicaid, little is known about the effects of this policy change on access to care and health outcomes. This is the first study, to our knowledge, to consider the effect of disenrollment on stage at diagnosis and delay in surgery for breast cancer. Methods: We use 2002-2008 data from Tennessee Cancer Registry which collects data on newly diagnosed cases of malignant disease that occur to Tennessee residents from all hospitals, laboratories, facilities and healthcare practitioners. The sample used for this study consists of women aged 21 to 64 who were diagnosed with breast cancer and living in Tennessee during the period of study. We merge data on zip code median income with the Tennessee Cancer Registry data and estimate a difference-in-differences model. We calculate the changes in stage at diagnosis, more than 60-days delay in surgery, and more than 90-days delay in surgery for female breast cancer among women who were diagnosed with breast cancer and had surgery as the first-line treatment. The difference-in-differences model compares women who were living in low-income zip codes (and thus more likely to be subject to disenrollment) with women who lived in high-income zip codes before and after Tennessee's 2005 Medicaid disenrollment. We control for age, race/ethnicity, marital status, insurance coverage, and year fixed effects. Results: Preliminary results suggest that nonelderly women who lived in low-income zip codes were 2.8 percentage points (p < 0.1) more likely to be diagnosed with late stage (regional or distant) breast cancer, compared to women living in high-income zip codes, after Tennessee's Medicaid disenrollment. In addition, nonelderly women who lived in low-income zip codes were 1.9 percentage points (p < 0.05) less likely to have more than 60-days delay in surgery than women living in high-income zip codes, after the disenrollment. Women who lived in low-income zip codes were also more likely to have more than 90-days delay in surgery, but this difference was not significant. Conclusions: While many states are expanding Medicaid eligibility under the Affordable Care Act, there has been discussion among policymakers in some states to reduce eligibility once full federal funding expires. This study provides evidence on the potential impact of Medicaid disenrollment on delays in diagnosis and performing urgent surgeries to treat late stages of breast cancer among low-income women in states that may consider future changes to Medicaid eligibility. Citation Format: Wafa W. Tarazi, Cathy J. Bradley, Harry D. Bear, David W. Harless, Lindsay M. Sabik. Medicaid disenrollment in Tennessee and disparities in stage at diagnosis and surgery for female breast cancer. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A82.

Abstract P5-08-02: Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%

Abstract Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha'emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of <18, 18-30, ≥31): low (51%), intermediate (38%), and high (11%), with chemotherapy (CT) use of 1%, 26%, and 89%, respectively. Distant recurrence was reported in 17/813, 33/612, and 24/169 patients in the low, intermediate, and high Recurrence Score groups, respectively. In the high Recurrence Score group, distant recurrence was reported in 20/150 (13.3%) of CT-treated patients and in 4/19 (21.1%) of untreated patients. In the intermediate Recurrence Score group, the respective values were 9/162 (5.6%) and 24/450 (5.3%). The 5-year KM estimate for distant recurrence rate was 1.4% (95% CI: 0.9-2.3%) for the entire cohort, and 0.5% (95% CI: 0.2-1.6%), 1.2% (95% CI: 0.6-2.8%), and 6.9% (95% CI: 3.7-12.9), for the low, intermediate, and high Recurrence Score groups, respectively. The 5-year KM estimate for breast cancer specific survival was 98.4% (95% CI: 97.6-98.9%) for the entire cohort, and 99.9% (95% CI: 99.0-99.98%), 98.5% (95% CI: 97.1-99.2%) and 90.6% (95% CI: 84.5-94.4%), for the low, intermediate, and high Recurrence Score groups, respectively. Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-02.

Abstract P6-09-11: Independent prognostic value of age depends on breast cancer subtype

Abstract Background: Young women present more often with aggressive breast cancer phenotypes and have worse prognosis. It remains controversial whether age is an independent prognostic factor in early stage breast cancer. Arbitrarily chosen age cut-off values have been proposed in different studies. Furthermore, few studies have examined the impact of breast cancer subtypes on the prognostic value of age. This abstract represents an update of a prior analysis (San Antonio Breast Cancer Symposium, December 4-8 2012, P06-07-29). Methods: We included all primary operable female breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We assessed the effect of age on locoregional free interval (LRRFI), distant metastasis interval (DMFI) and breast cancer specific survival (BCSS). In univariate analysis, using Cox regression models, we determined the best categorization of age at diagnosis into two or three age groups by considering all possible combinations of cut-off values. Best categorization was obtained with three age groups. We further determined, using multivariate analysis (correcting for phenotype, tumor size, nodal status, adjuvant chemo -, hormone – and radiotherapy, type of surgery and procedure of axillary staging), whether age at diagnosis remains an independent predictor of outcome (LRRFI, DMFI and BCSS). We further explored whether age at diagnosis is an independent predictor of event risk (LRRFI, DMFI and BCSS) in different breast cancer subtypes. Luminal A-like (grade I or II, ER and/or PR positive, HER 2 positive), Luminal B-like (idem but grade III), Luminal HER 2 like (ER and/or PR positive, HER 2 positive), HER 2 like (ER/PR negative, HER 2 positive), triple negative (ER/PR negative, HER 2 negative). Results: We included 4180 patients with a mean/median age of 58/57 year and with a median follow up of 8.9 year. Multivariate analysis confirmed age as an independent prognostic variable for LRRFI, DMFI and BCSS. Results multivariable analysis with age in 3 groups (HR (95% CI) P-VALUE) LRRFIDMFIBCSSYoungest versus middle1.61 (1.18-2.18) 0.00251.54 (1.23-1.93) 0.00021.72 (1.26-2.36) 0.0007Youngest versus oldest3.45 (1.85-6.45) 0.00011.25 (0.89-1.77) 0.19821.31 (0.85-2.02) 0.2220Middle versus oldest2.15 (1.22-3.79) 0.00820.81 (0.61-1.09) 0,17060.76 (0.55-1.06) 0.1014 We found optimal cut-off values for LRRFI at 44y and 72y, for DMFI at 47y and 71y and for BCSS at 41y and 70y. In an exploratory analysis, with age as continuous variable, by subtype we found a significant independent association between age and LRRFI (P=0.0169), DMFI (P=0.0344) in luminal A-like, LRRFI (P=0.0022) in luminal B-like and DMFI (P=0.0010) and BCSS (P=0.0053) in triple negative breast cancer. No significant associations were found in luminal HER2 and HER2 like breast cancers. Conclusion: This study has shown that young age is an independent prognostic factor for LRRFI, DMFI and BCSS after correction for the most important clinical prognostic factors. The prognostic effect is most important in luminal A and triple negative subtypes. Additional analyses for subtypes with age as a categorical variable will be performed and optimal cut off values will be defined. Citation Format: Poppe A, Brouckaert O, Laenen A, Soubry A, Remmerie C, Floris G, Leunen K, Berteloot P, Amant F, Vergote I, Nevelsteen I, Smeets A, Christiaens M-R, Weltens C, Peeters S, Van Limbergen E, Wildiers H, Neven P. Independent prognostic value of age depends on breast cancer subtype. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-11.

Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring.

There is a paucity of immune signatures identifying patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer (IBC) at risk for treatment failure following trastuzumab and chemotherapy. To determine whether circulating anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity correlates with recurrence in patients with completely treated HER2-positive IBC. Hypothesis-generating exploratory translational analysis at a tertiary care referral center of patients with completely treated HER2-positive IBC with median (interquartile range) follow-up of 44 (31) months. Anti-HER2 Th1 responses were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II-promiscuous peptides via interferon-γ (IFN-γ) enzyme-linked immunospot assay. T-helper type 1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFCs]/106 cells). Anti-HER2 Th1 responses in treatment-naive patients (used as an immunologic baseline) were compared with those in patients completing trastuzumab and chemotherapy; in the latter group, analyses were stratified by recurrence status. Recurrence was defined as any locoregional or distant breast event, or both. Cox regression analysis estimated the instantaneous hazard of recurrence (ie, disease-free survival [DFS]) stratified by anti-HER2 Th1 responsivity. In 95 women with HER2-positive IBC (median [range] age, 49 [24-85] years; 22 treatment-naive, 73 treated with trastuzumab and chemotherapy), depressed anti-HER2 Th1 responsivity (recurrence, 2 of 25 [8%], vs nonrecurrence, 40 of 48 [83%]; P < .001), mean (SD) repertoire (0.1 [0.1] vs 1.5[0.2]; P < .001), and mean (SD) cumulative response (14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence (n = 25) compared with patients without recurrence (n = 48). After controlling for confounding, anti-HER2 Th1 responsivity remained independently associated with recurrence (P < .001). This immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (Th1)-not CD4+GATA-3+IFN-γ+ (Th2) or CD4+CD25+FoxP3+ (Treg)-phenotypes, and not attributable to immune incompetence. When stratifying trastuzumab plus chemotherapy-treated patients by Th1 responsivity, Th1-nonresponsive patients demonstrated a worse DFS (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients (hazard ratio, 16.9 [95% CI, 3.9-71.4]; P < .001). Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.

Solid papillary carcinoma of the breast: A special entity needs to be distinguished from conventional invasive carcinoma avoiding over-treatment

IntroductionSolid papillary carcinoma of the breast, a newly-defined entity, is poorly recognized, and its nature and management is still debated. Material and methodsEleven cases of pure solid papillary breast carcinoma in our archive and 253 cases reported in previous literature were retrospectively analyzed for their clinicopathological features and outcomes. ResultsThe eleven cases occurred in elderly females. Grossly, all tumors were well-circumscribed and typically composed of solid papillary nodules. The tumor cells were bland-looking with low-grade atypia and mitoses < 5/10HPF. Immunophenotypically, all eleven cases showed positivity for ER and PR, negativity for CK5/6 and HER2, and a low proliferative index of Ki67. Five cases showed scattered positivity for myoepithelial marker p63, and four cases were positive for CK5/6 and CD10 around the nodules, whereas the other cases were completely negative for all myoepithelial markers. Five cases expressed the neuroendocrine marker synaptophysin, and six cases expressed chromogranin. In nine cases, mastectomy and axillary lymph nodes excision were performed, and only one showed micrometastasis in an axillary lymph node. There was no local recurrence or distant metastasis or breast carcinoma related-death during the follow-up periods of 50 months. Out of 253 solid papillary breast carcinomas reported in literature, the percentage of axillary lymph node metastasis was 4/136 (3%), with rare local recurrences and distant metastasis; only three patients died of breast carcinoma. ConclusionSolid papillary carcinoma of the breast is a rare entity with distinctive clinicopathological features and excellent prognosis and should be distinguished from conventional breast carcinoma to avoid over-treatment.

Geographical Location and Stage of Breast Cancer Diagnosis: A Systematic Review of the Literature.

To examine systematically the literature on the effect of geographical location variation on breast cancer stage at diagnosis, race/ethnicity, and socioeconomic status. Eight electronic databases were searched using combination of key words. Of the 312 articles retrieved from the search, 36 studies from 12 countries were considered eligible for inclusion. This review identified 17 (47%) of 36 studies in which breast cancer patients residing in geographically remote/rural areas had more late-stage diagnosis than urban women. Ten (28%) studies reported higher proportions of women diagnosed with breast cancer resided in urban than rural counties. Nine (25%) studies reported no statistically significant association between place of residence and stage at diagnosis for breast cancer patients residing in rural and urban areas. Cancer patients residing in rural and disadvantaged areas were more likely to be diagnosed with distant breast metastasis. Efforts to reduce these inequalities and subsequent mortality are needed.

Use of Palliative Endocrine Therapy in Patients with Hormone Receptor-Positive Distant Metastatic Breast Cancer: How Often, How Effective, How Long?

Background: This study provides real-world clinical evidence regarding palliative endocrine therapy (ET) in breast cancer (BC). The main questions to be answered were: how often and how long did patients receive ET? A particular aspect was the analysis of compliance and persistence with ET. Methods: An analysis of a nonselected/consecutive cohort of women with distant metastatic hormone receptor-positive BC (n = 205) was conducted. Results: In all, 165 patients (80.5%) received ET during the palliative disease course. The noncompliance rate was 1.5%. Sixty-seven patients (40.6%) had ET as the only antineoplastic therapy. The median number of therapy lines was 2, and the median duration was 18 months. The median metastatic disease survival (MDS) was 34 months. In patients who had an MDS of ≥9 months (n = 145; 87.9%), during 70.6% of the MDS time only ET had been administered. Patients who were naïve to ET more often had a good response to and a longer duration of palliative ET than those who were not. The nonpersistence rate was 4.3%. Conclusions: Excluding the few patients who had a rapidly progressive course, the disease was controlled for about 70% of the entire palliative disease course with ET alone. Only very few patients were nonpersistent with ET and consciously stopped a still effective, ongoing ET.

Breast Cancer Patients Undergoing Sentinel Node Biopsy: Additional Axillary Tumor Burden as a Function of the Total Number of Excised Sentinel Nodes—A Multicenter Study

BackgroundRecent studies have challenged the long-standing assumption that breast cancer prognosis is determined by lymph node regional status. We assessed locoregional relapse, distant metastases, and mortality alongside additional axillary disease in breast cancer patients undergoing sentinel node (SN) biopsy. Patients and MethodsThis prospective study assessed 1070 women with clinical T1-T2 invasive breast cancer with negative clinical/ultrasound axillae. ResultsA total of 25.1% of patients had positive SN biopsy findings, of whom 69.2% had only 1 involved SN. The rate of axillary recurrence was 0.7%, with no significant differences found between patients with positive or negative SN (0.6% vs. 1.1%). There were also no significant differences in the rate of distant metastases or breast cancer–specific mortality. If we had applied the Z0011 trial suggestions, residual axillary disease would have reached 16.2%: 13.5% in patients over 50% and 21.3% in patients under 50. The rate of residual axillary disease would have been 25.2% in patients with only 1 SN (20.2% in patients over 50% and 38.2% in patients under 50). In patients with 2 SN, residual disease would have ranged from 12.0% in patients over 50% to 19.0% in patients under 50. From 3 SN on, residual disease seems negligible. ConclusionThere were no significant differences in locoregional relapse, distant metastases, or mortality between patients with negative and positive SN. Patients with 3 or more SN have no additional axillary disease. In patients younger 50, one must be extremely cautious if the Z0011 suggestions are to be applied, especially if there is only 1 SN.

Treatment differences between urban and rural women with hormone receptor-positive early-stage breast cancer based on 21-gene assay recurrence score result.

Breast cancer is the most common invasive cancer in women in the United States, and the second leading cause of cancer death.1 Differences in breast cancer mortality have been linked to socioeconomic and population differences, but the etiologic relationship among these factors remains unclear.2 Although some studies have found that rural populations have an increased overall breast cancer-associated mortality,2 others have suggested decreased mortality3 or no difference after adjusting for age, sex, or race.4,5 Proposed factors that possibly contribute to increased mortality in rural patients include presentation with later stage dis-ease,4,6,7 less access to mammographic screening,8,9 lower socioeconomic status,10 and less access of because of geographic location to newer more effective therapies and technologies.11,12 Individual risk factors13,14 such as body mass index (BMI),15,16 parity,13 or differences in exogenous hormone use17 may also contribute. Finally, regardless of predisposing risk factors, women from different population settings may choose or receive different treatment modalities for similarly staged cancers.11,13 It remains unclear whether tumor biology or treatment factor differences drive these population mortality differences. Comparing breast cancer prognostic characteristics might be hypothesis-generating with regard to whether differences in inherent tumor biology drive these population mortality differences. The 21-gene assay (Oncotype DX) predicts the 10-year risk of distant breast cancer recurrence in patients with estrogen receptor-positive (ER-positive), human epidermal growth factor receptor 2 (HER2) negative early-stage breast cancer (EBC) based on testing of tumor tissue.18 Te assay has been commercially available since 2004 in hormone receptor-positive (HR-positive ) breast cancer and is used in clinical practice.19 Recurrence scores on the assay range from 0-100, with lower results correlated with less risk of distant recurrence.18 Patients can be divided into 3 groups based on the assay scores: low, intermediate, or high risk. Te high-risk group (score results, >31) is likely to benefit from chemotherapy, whereas the low-risk group (<18) does not benefit.20-22 Current recommendations for the intermediate-risk group (18-30) include offering chemotherapy,23,24 although the risk reduction from chemotherapy in this group remains uncertain. An ongoing study (TAIL0Rx/PACCT-01) is specifically designed to answer whether chemotherapy benefits women with node-negative HR-positive EBC with an intermediate score result. TAILORx is expected to report results in 2017.25 Differences between rural and urban populations on the basis of recurrence scores have not been reported. Score results may offer insight into prognostic differences between rural and urban women who present with breast cancers of similar stage and receptor-status. Therefore, we retrospectively assessed rural and urban differences by recurrence scores to understand possible causes for rural-urban differences in breast cancer outcomes such as overall breast cancer-associated mortality. Secondary objectives included assessing rural and urban differences in other risk factors as well as therapies received based on recurrence score.

Abstract P6-08-05: Prognostic value of the progesterone receptor by proliferation rate in patients with luminal HER2 negative breast cancer

Abstract Background Estrogen receptor (ER) positive, HER2 negative breast cancer (BC) can be classified into luminal A and luminal B-like tumors according to tumor grade. Several evidences point to the fact that IHC expression of the progesterone receptor (PR) has prognostic value. In this study, we assess to what extent a negative PR in luminal A BCs increases the risk of distant metastasis and whether or not luminal B BC might have a good prognosis if PR is positive. Patients and methods Women with primary operable ER positive, HER2 negative BC treated at University Hospitals Leuven between 2000 and 2009 were retrieved from our database. So called luminal A tumors were defined as grade 1-2 BC, whereas so called luminal B BC were defined as grade 3 BC. Distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) were investigated by their PR status. PR was considered negative if the semi-quantitative Allred score was 0-2. Before 2003 the semi-quantitative H-score was used and a score &amp;lt;50 was considered negative. Statistical analysis for DMFI was performed using the cox proportional hazards regression. For BCSS we used Fine &amp; Gray’s competing risk regression. Covariates were age at diagnosis, tumor size, lymph node status, and therapy. Results In total, 3294 patients from Leuven were analyzed. From this cohort, 285 patients experienced metastases (8.7%) and 172 patients died of BC (5.2%). Details are shown in Table 1. The median age at diagnosis was 58 years with ages ranging from 22 to 95 years, 2358 patients (71.6%) were aged above 50 at diagnosis. The median follow-up period was 8.1 years. Table 1: Number of patients that metastasized and died of BC by luminal subgroup and PR status. MetastasesBC-related deathluminal APR positive110/2103 (5%)61/2103 (3%) PR negative16/267 (6%)9/267 (3%)luminal BPR positive120/786 (15%)75/786 (10%) PR negative39/138 (28%)27/138 (20%)BC: breast cancer, PR: progesterone receptor In Leuven, the reduction in risk of metastasis in patients with PR positive luminal A and luminal B BC was respectively 14% (Hazard ratio (HR): 0.86, 95% confidence interval (CI) 0.52-1.51) and 47% (HR: 0.53, 95% CI 0.37-0.78) compared with PR negative tumors. PR positive luminal A and luminal B BC patients had a 16% (HR: 0.84, 95 % CI 0.42-1.69) and 53% (HR: 0.47, 95% CI 0.30-0.75) reduction in the risk of BC-related death compared with PR negative tumors respectively. The same analysis was also carried out for postmenopausal patients (older than 50 years) only. In this subcohort, PR positivity was associated with a 9% (HR 0.91, 95% CI 0.50 to 1.83) and 59% (HR 0.41, 95% CI 0.28 to 0.63) reduction in the risk of metastatic events in luminal A and luminal B lesions, respectively. For BCSS, a 31% (HR 0.69, 95% CI 0.30 to 1.57) and 66% (HR 0.34, 95% CI 0.20 to 0.57) reduction in the risk of BC-related death for respectively PR positive luminal A and luminal B BC patients was found. Conclusion These results suggest that the prognostic effect of PR in primary operable BC depends on the tumor grade. Compared with luminal PR negative BC, PR positivity improves outcome more in luminal B than in luminal A lesions. Citation Format: Kathleen Van Asten, Ben Van Calster, Anneleen Lintermans, Olivier Brouckaert, Giuseppe Floris, Hans Wildiers, Patrick Neven. Prognostic value of the progesterone receptor by proliferation rate in patients with luminal HER2 negative breast cancer [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 P6-08-05.

Abstract S3-08: Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Analysis of the SOFT trial

Abstract Background It is uncertain if the addition of OFS to adjuvant endocrine therapy with T improves outcomes in premenopausal HR+ BC. The SOFT trial was designed to determine the value of OFS in women who remain premenopausal and are treated with T (OFS question) and also to test whether an AI improves outcome in premenopausal women with HR+ BC treated with OFS (AI question). In the combined analysis of the TEXT and SOFT trials (AI question), the group treated with the AI exemestane+OFS had a significantly better disease-free survival (DFS) than those with T+OFS. This abstract presents the results of the OFS question (n=2,045). Patients and Methods Between November 2003 and January 2011, the SOFT phase 3 trial randomized 3066 premenopausal women with HR+ BC to 5 years of adjuvant endocrine therapy with exemestane+OFS versus T+OFS versus T alone, with OFS initiated by choice of GnRH agonist triptorelin, oophorectomy or ovarian irradiation. Prior chemotherapy was allowed, provided women had confirmed premenopausal estradiol levels within 8 months of completing chemotherapy. The primary end point was DFS which included invasive local, regional, distant and contralateral breast events, second non-breast malignancies and deaths without prior cancer. Because of a lower-than expected overall event rate and to ensure results within a reasonable time-frame, a protocol amendment in 2011 changed the originally event-driven analysis plan. The amendment (1) designated the comparison of T+OFS versus T alone as the primary analysis for SOFT (n=2045), recognizing that the statistical power for the original three pairwise comparisons would be substantially reduced and (2) specified that the primary analysis of T+OFS versus T be undertaken when median follow-up was at least 5 years. The comparison would be tested at the 2-sided 0.05 level with no interim analysis. Based on the projected number of events at the lower rates, the estimated power to detect hazard ratios of 0.75, 0.70, and 0.66 for the comparison would be 52%, 69%, and 80%. Results The SOFT trial completed planned patient enrollment with an international collaboration involving 426 centres from BIG and NABCG led by the International Breast Cancer Study Group (IBCSG). Numbers of patients randomized, randomization strata, and pt age are summarized in the Table. The database lock for the primary analysis of the OFS question will occur in September 2014 and the final analysis will be completed by October 15, 2014. SOFT Patients (%)Tamoxifen alone1021 (33%)Tamoxifen+OFS1024 (33%)Exemestane+OFS1021 (33%)* Prior Chemotherapy54%Lymph node positive35%Median age (% &amp;lt; 40 years)43 years (30%)*Patients randomized to Exemestane+OFS are not part of the current analysis Conclusions We will present the primary analysis of outcomes and toxicities by treatment for women randomized to receive T+OFS versus T and address the value of OFS in addition to T as adjuvant endocrine therapy for premenopausal women with HR+ BC. Citation Format: Aron Goldhirsch, Richard D Gelber, Prudence A Francis, Meredith M Regan, Gini F Fleming, Istvan Lang, Eva M Ciruelos, Meritxell Bellet, Herve Bonnefoi, Miguel A Climent, Lorenzo Pavesi, Harold J Burstein, Silvana Martino, Nancy E Davidson, Charles E Geyer Jr, Barbara A Walley, Robert E Coleman, Pierre Kerbrat, Manuela Rabaglio-Poretti, Alan S Coates. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Analysis of the SOFT trial [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 S3-08.

Abstract P5-21-01: Effect of adjuvant systemic therapy in reducing rates of loco-regional recurrence in early-stage breast cancer: Results from nine NSABP randomized phase III trials

Abstract Background Adjuvant systemic therapy reduces risk of distant recurrence (DR) and breast cancer death. In addition, adjuvant systemic therapy reduces risk of loco-regional recurrence (LRR). We examined the magnitude of the effect of adjuvant systemic therapy (tamoxifen, chemotherapy, and chemotherapy + trastuzumab) in reducing incidence rates and cumulative incidence rates of LRR as first event in nine recent NSABP randomized trials that were conducted from 1981 to 2005 and included a total of 21,815 patients. Methods Nine NSABP clinical trials of adjuvant (or neoadjuvant) systemic therapy, in which a reduction in LRR or DR was observed, were included in the analysis (NSABP B-13, B-14, B-19, B-20, B-21, B-27, B-28, B-30, and B-31). The cumulative incidence rates of LRR as the first disease-free survival (DFS) event were estimated and compared across treatment arms via log-rank tests. The sub-distribution proportional hazards models were applied to estimate the reduction in incidence rate of LRR from adjuvant systemic therapies. The corresponding magnitude of reduction in the incidence rate of any DFS event was estimated from Cox proportional hazards models. Results Across all nine clinical trials, adjuvant systemic therapy resulted in reductions in LRR that were comparable to or greater than the reductions in DFS events (Table). The observed reductions in LRR with adjuvant chemotherapy were of greater magnitude in trials of node-negative patients (35-58%) than in trials of node-positive patients (13-15%). Reductions in LRR were of similar magnitude with adjuvant chemotherapy as with adjuvant tamoxifen. In B-27, the sequential addition of neoadjuvant or adjuvant docetaxel to neoadjuvant AC reduced LRR rates by 27%. The addition of trastuzumab to adjuvant chemotherapy decreased LRR rates by 34%. Conclusions Rates of LRR have steadily declined over time in NSABP adjuvant clinical trials. This decline can be attributed to improvements in surgical and radiotherapy techniques but is also the result of the use of increasingly effective adjuvant systemic therapy. NSABP TrialPopulationTreatment ComparisonHR(95%CI)DFSHR(95%CI)LRR10-yr Cum Incidence of LRR(%)Log rank p-valueB-13 (n=1,084)N(-) / ER(-)MF v No Adj Rx0.66 (0.55,0.79)0.42 (0.29-0.62)5.9 v 13.5&amp;lt;0.001B-14 (n=4,028)N(-) / ER(+)TAM v Placebo0.70 (0.65, 0.77)0.54 (0.45-0.66)5.2 v 11.2&amp;lt;0.001B-19 (n=1,074)N(-) / ER(-)CMF v MF0.69 (0.57, 0.84)0.48 (0.31-0.73)5.3 v 10.0&amp;lt;0.001B-20 (n=2,299)N(-) / ER(+)CMF/MF+TAM v TAM0.76 (0.66, 0.88)0.57 (0.41-0.78)3.7 v 7.1&amp;lt;0.001B-21 (n=645)N(-) / ≤1cmTAM v Placebo0.93 (0.71, 1.21)0.65 (0.38-1.09)4.7 v 8.80.10B 27 (n=2,346)Operable T1-3 N0-1AC→T v AC (neoadj)0.92 (0.81, 1.05)0.73 (0.56-0.94)9.1 v 12.20.015B-28 (n=3,036)N(+)AC→P v AC0.90 (0.81, 1.00)0.87 (0.69-1.1)8.6 v 10.00.24B-30 (n=5,240)N(+) / HER2(-)AC→T v AT/TAC0.84 (0.76, 0.93)0.85 (0.65-1.1)4.6 v 5.40.23B-31 (n=2,063)N(+) / HER2(+)AC→P+H v AC→P0.59 (0.50, 0.69)0.66 (0.46-0.94)5 v 7.40.02N: Node; M: Methotrexate; F: 5-FU; TAM: Tamoxifen; C: Cyclophosphamide; A: doxorubicin; T: Docetaxel; P: Paclitaxel; H: trastuzumab Citation Format: Eleftherios P Mamounas, Gong Tang, Qing Liu, Jong-Heyon Jeong, Thomas B Julian, Priya Rastogi, Charles E Geyer, Sandra M Swain, Soonmyung Paik, D Lawrence Wickerham, Joseph P Costantino, Norman Wolmark. Effect of adjuvant systemic therapy in reducing rates of loco-regional recurrence in early-stage breast cancer: Results from nine NSABP randomized phase III trials [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 P5-21-01.

Abstract P4-02-09: RUNX3 hypermethylation in circulating tumor DNA is a biomarker of breast cancer distant metastasis

Abstract Breast cancer detection has not resulted in the expected decrease in mortality suggesting that current screening strategies are not finding metastasis-prone lesions before metastasis occurs and instead are detecting many lesions that will not progress to metastatic disease. Although several improvements in the management of breast cancer have been made, an estimated 90% of breast cancer related deaths are due to the development of distant metastasis to organs such as lung, bone, liver, and brain. Metastatic breast cancer affects 10-15% of breast cancer patients, is often refractory to therapy and associated with poor outcomes. However, a blood test indicating a high-risk population at the time of breast cancer diagnosis might shift the current strategy and improve outcomes. Efforts for identifying predictive markers of breast cancer metastasis have been impeded by a lack of data defining the genetic and epigenetic determinants of the disease. Numerous studies suggest that DNA methylation could be a useful biomarker for improving the clinical management. Recently circulating tumor (ct)DNA has attracted attention for clinical use in the context of risk prediction, prognostication and prediction in human cancer. Various types of DNA alterations have been reported in ctDNA but methylated DNAs are chemically stable and are among the most sensitive and specific ctDNA cancer markers. The objective of our study was to identify and validate a blood-based DNA methylation biomarker for breast cancer patients at high risk of distant metastasis. Using the HumanMethylation27K bead array, we recently identified RUNX3 hypermethylation involving 3 CpG probes in 32 breast brain metastasis tumor tissue compared to a series of 50 unmatched early stage breast cancer samples. We calculated the area under the curve (AUC) to exceed 0.8, with a higher AUC achieved in Her2-positive samples. In an independent, first of its kind analysis, we performed whole genome bisulfite sequencing (WGBS) of ctDNA from plasma samples representing three pools of 40 women with distant metastatic breast cancer to various organs, 40 women with metastasis-free breast cancer, and 40 non-breast cancer controls. In this unbiased analysis, these data demonstrated RUNX3 hypermethylation in the plasma of patients with metastatic breast cancer in the same region corresponding to the CpG probes of the methylation array. We are now performing bisulfite pyrosequencing of each individual plasma sample, and in an additional cohort of 50 archival primary/brain metastasis tumor pairs with matching serum and clinical outcomes data. To determine regional specific differences we have also selected two additional regions of RUNX3 not differentially methylated for validation by bisulfite pyrosequencing. Determining the extent to which RUNX3 hypermethylation occur in the context of brain metastasis versus other distant sites are ongoing studies. Together these studies point towards RUNX3-regional specific methylation as a potential blood-based biomarker of breast cancer metastasis. Such a biomarker will help establish surveillance methods and eventually preventative regimens that will increase the likelihood of long-term progression-free survival for breast cancer patients at risk of distant relapse. Citation Format: Bodour Salhia, Gerald C Gooden, Kyle N Johnson, Waibhav Tembe, Garrick Wallstrom, Winnie Liang, Manmeet Ahluwalia, Steven N Kalkanis, Tom Mikkelsen, Steven A Toms. RUNX3 hypermethylation in circulating tumor DNA is a biomarker of breast cancer distant metastasis [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 P4-02-09.

Promoter hypermethylation profiling of distant breast cancer metastases.

Promoter hypermethylation of tumor suppressor genes seems to be an early event in breast carcinogenesis and is potentially reversible. This makes methylation a possible therapeutic target, a marker for treatment response and/or a prognostic factor. Methylation status of 40 tumor suppressor genes was compared between 53 primary breast tumors and their corresponding metastases to brain, lung, liver, or skin. In paired analyses, a significant decrease in methylation values was seen in distant metastases compared to their primaries in 21/40 individual tumor suppressor genes. Furthermore, primary tumors that metastasized to the liver clustered together, in line with the finding that primary breast carcinomas that metastasized to the brain, skin, or lung, showed higher methylation values in up to 27.5 % of tumor suppressor genes than primary carcinomas that metastasized to the liver. Conversion in methylation status of several genes from the primary tumor to the metastasis had prognostic value, and methylation status of some genes in the metastases predicted survival after onset of metastases. Methylation levels for most of the analyzed tumor suppressor genes were lower in distant metastases compared to their primaries, pointing to the dynamic aspect of methylation of these tumor suppressor genes during cancer progression. Also, specific distant metastatic sites seem to show differences in methylation patterns, implying that hypermethylation profiles of the primaries may steer site-specific metastatic spread. Lastly, methylation status of the metastases seems to have prognostic value. These promising findings warrant further validation in larger patient cohorts and more tumor suppressor genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3362-y) contains supplementary material, which is available to authorized users.

Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer

BackgroundNo single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.MethodsWe performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.ResultsThe median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.ConclusionsAmong women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.)

Increase in Distant Stage Breast Cancer Incidence Rates in US Women Aged 25-49 Years, 2000-2011: The Stage Migration Hypothesis.

Background. Unexplained increases have been reported in incidence rates for breast cancer diagnosed at distant stage in younger U.S. women, using data from the Surveillance, Epidemiology and End Results (SEER) Program. Methods. This report focused on recent SEER trends (2000–2011) in age-standardized incidence rates of invasive breast cancer at ages 25–39 and 40–49 years and the hypothesis that stage migration may have resulted from advances in detecting distant metastases at diagnosis. Results. Increases in the rates for distant stage were roughly equal to decreases in the rates for the most advanced stage subgroups within regional stage; this was evident for estrogen receptor (ER) negative cancers, associated with poorer prognosis, but not for ER positive cancers. The 3-year relative survival rate increased over time for distant stage (especially in the ER positive subgroup) and regional stage but not for localized stage; these trends do not contradict the stage-migration hypothesis. Conclusions. Findings provide some support for stage migration as one explanation for the recent increase in incidence of distant stage breast cancer, but additional studies are needed using other databases.