Positive Hormone Receptor Status Research Articles

ACE et diagnostic précoce de récidive dans les différents sous-types moléculaires de cancer du sein : comparaison au CA 15-3

This retrospective study evaluates the interest of CEA measurement for early detection of breast cancer recurrences. Among 804patients with invasive breast cancer, we selected 97patients without recurrence (WR) for 5years or more, 32with a local recurrence (LR) and 131with at least one distant metastasis (DM). Elevated CEA and CA15-3levels (>3.1μg/L and >26kU/L respectively) were found in 6% and 22% of patients with RL respectively and in 49% and 69% of patients with DM. Both CEA and CA15-3retained a significant value in predicting DM by univariate and multivariate analysis. Higher sensitivity of CEA and CA15-3were found in tumors with positive hormonal receptor status. CEA and CA15-3levels at DM were raised respectively in 23and 65% of the triple negative group, 58and 75% of the luminal, 56and 78% of the luminal-HER2and 50and 30% of HER2-enriched group (P=0.0094and 0.0252respectively). The combination of CEA and CA15-3increased CA15-3sensitivity in especially luminal and HER2-enriched groups. In conclusion, elevated CA15-3and CEA levels at initial diagnosis of recurrence were found to be associated with hormonal receptor status and breast cancer subtypes. The combination of CEA and CA15-3appeared useful especially luminal and HER2-enriched groups.

DNA methylation and hormone receptor status in breast cancer.

BackgroundWe examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA).ResultsDNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity.ConclusionsHigher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0184-7) contains supplementary material, which is available to authorized users.

Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer

Abstract Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material &amp; Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p&amp;lt;0.001)) and TCH (HR=0.76, 95% CI [0.65, 0.90]; p&amp;lt;0.001). At this final analysis, the DFS HRs for AC-TH and TCH are closer than those observed in any prior protocol-directed study analyses (at 5 years follow-up the HRs were 0.64 and 0.75 for AC-TH and TCH respectively). Also, an OS benefit was observed in both AC-TH (HR=0.64, 95% CI [0.52, 0.79]; p&amp;lt;0.001)) and TCH (HR=0.76, 95% CI [0.62, 0.93]; p=0.0081). Importantly, TCH has significantly lower symptomatic CHF events by five-fold compared to AC-TH; 21 (2.0%) for AC-TH vs. 4 (0.4%) for TCH; p=0.0005. The AC-T control arm had 8 (0.8%) symptomatic CHF events. The incidence of patients with a relative LVEF decline &amp;gt;10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p&amp;lt;0.0001). Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bée-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [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 S5-04.

Clinical predictors of long-term survival in HER2-positive metastatic breast cancer.

Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9years (95% CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33%) survived for 5 or more years and 12 (7%) survived more than 10years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14%) survived more than 5years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7% of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.

Male breast cancer: a clinicopathological study of an Egyptian population (Alexandria experience).

Aim of the studyThe purpose of this retrospective study is to evaluate the clinicopathological features and treatment results of male breast cancer presented to our tertiary referral center.Material and methodsBetween January 1998 and December 2005, a total of 39 men with breast cancer treated at Alexandria Main University Hospital and their medical records were reviewed.ResultsThe median age of patients was 59 years. Only 3 (7.7%) patients had positive family history. All patients presented by breast swellings that were associated with axillary mass in about one third of them. Around 80% had hormone receptor positive (estrogen and/or progesterone receptors). Two third of patients had advanced T-stage (T3 and T4). Left sided breast cancer occurred in 51.3%. Infiltrating ductal carcinoma was the most common type of histology encountered and grade 2 was the predominant grade of tumor. Modified radical mastectomy was the most common (87.2%) type of surgery done followed by chemotherapy for 32 patients and loco-regional radiotherapy for 20 patients. Tamoxifen was administered in 31 patients. Distant relapse occurred in 7 patients (17.9%) and local recurrence occurred in 2 patients (5.1%). The 5-year disease-free survival (DFS) was 82% and the 5-year overall survival (OS) rate was 84%. Only negative axillary lymph node and positive hormone receptor status were significantly associated with favorable DFS and OS. T-stage, grade of tumor and type of chemotherapy given had no statistically significant impact on either DFS or OS.ConclusionsMale breast cancer is still under-investigated and further researches are warranted.

The Distinct Gene Regulatory Network of Myoglobin in Prostate and Breast Cancer.

Myoglobin (MB) is not only strongly expressed in myocytes, but also at much lower levels in different cancer entities. 40% of breast tumors are MB-positive, with the globin being co-expressed with markers of tumor hypoxia in a proportion of cases. In breast cancer, MB expression is associated with a positive hormone receptor status and patient prognosis. In prostate cancer, another hormone-dependent cancer type, 53% of tumors were recently shown to express MB. Especially in more aggressive prostate cancer specimen MB expression also correlates with increased patient survival rates. Both findings might be due to tumor-suppressing properties of MB in cancer cells. In contrast to muscle, MB transcription in breast and prostate cancer mainly depends on a novel, alternative promoter site. We show here that its associated transcripts can be upregulated by hypoxia and downregulated by estrogens and androgens in MCF7 breast and LNCaP prostate cancer cells, respectively. Bioinformatic data mining of epigenetic histone marks and experimental verification reveal a hitherto uncharacterized transcriptional network that drives the regulation of the MB gene in cancer cells. We identified candidate hormone-receptor binding elements that may interact with the cancer-associated MB promoter to decrease its activity in breast and prostate cancer cells. Additionally, a regulatory element, 250 kb downstream of the promoter, acts as a hypoxia-inducible site within the transcriptional machinery. Understanding the distinct regulation of MB in tumors will improve unraveling the respiratory protein’s function in the cancer context and may provide new starting points for developing therapeutic strategies.

Nuclear Gli1 expression is associated with pathological complete response and event-free survival in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant therapy.

Aberrant activation of the hedgehog (Hh) signaling pathway has shown predictive significance for treatment response and prognostic effect for survival in human tumors. However, the associations of the Hh signaling pathway with response to neoadjuvant therapy (NAT) and survival after NAT in breast cancer are unknown. Therefore, we investigated the correlation of pretherapeutic nuclear expression of glioma-associated oncogene homolog 1 (Gli1), a key transcriptional factor of the Hh signaling pathway, with pathological complete response (pCR) and event-free survival (EFS) in HER2-positive breast cancer treated with trastuzumab-based NAT. High nuclear Gli1 expression (OR 0.19; 95% CI 0.07-0.54; P = 0.002) and positive hormone receptor (HR) status (OR 0.36; 95% CI 0.14-0.90; P = 0.028) were independent and negative predictors of pCR in multivariate analysis. High nuclear Gli1 expression was significantly associated with lower pCR rates in both HR-positive and HR-negative tumors (P = 0.014 and 0.024, respectively). For survival analyses, multivariate analysis indicated that high nuclear Gli1 expression was the only independent predictor of poorer EFS in both the entire population (hazard ratio 2.97; 95% CI 1.18-7.44; P = 0.020) and patients with non-pCR (hazard ratio 3.98; 95% CI 1.35-11.68; P = 0.012). Our study is the first to demonstrate the associations of high nuclear Gli1 expression with resistance to trastuzumab-based NAT and subsequent worse prognosis in HER2-positive disease. These findings suggest that the nuclear Gli1 protein may be a novel target of NAT for HER2-positive breast cancer.

HER2-positivity rates in breast cancer: no variation over time when clinicopathological features and testing are stable.

HER2 status is essential for breast cancer subtyping and for systemic treatment decisions as patients with HER2-positive tumours can benefit from anti-HER2 targeted therapies. However, few data are available on the current HER2-positive breast cancers rate and its evolution across years. Using data from the Côte d'Or breast cancer registry, we identified, between 1998 and 2011, 3220 women with invasive breast cancer diagnosed in the same laboratory which carries out regular internal quality controls and participates in multiannual international quality control programmes. Throughout the studied period of time, despite an increase of annual breast cancer cases, HER2 positivity rate remained stable (13.1%; P=0.495), as did the proportion of tumours with positive hormone receptor status (P=0.467) and the proportion of SBR grade II/III tumours (P=0.747). Other characteristics, less strongly associated with HER2-positive status, showed either no annual variation (nodal and metastatic status, tumour size) or an annual positive trend (mean age, lobular carcinomas) or an annual negative trend (ductal carcinomas). These data reveal that in a population with stable clinical and pathological characteristics, and with the use of standardised assays, HER2 positivity rate remains stable over time. These results also emphasise that current HER2 positivity rate is lower than initially reported.

Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis

Enhancing the radiosensitivity of cancer cells is one of the most important tasks in clinical radiobiology. Endocrine therapy and radiotherapy are two cancer treatment modalities which are often given together in patients with locally-advanced breast cancer and positive hormone-receptor status. Oncostatic actions of melatonin are relevant on estrogen-dependent mammary tumors. In the present study, we wanted to evaluate the effects of the combination of ionizing radiation and melatonin on proteins involved in estrogen biosynthesis in breast cancer cells. We demonstrated a role of melatonin in mediating the sensitization of human breast cancer cells to the ionizing radiation by decreasing around 50% the activity and expression of proteins involved in the synthesis of estrogens in these cells. Thus, melatonin pretreatment before radiation reduces the amount of active estrogens at cancer cell level. Melatonin 1 nM induced a 2-fold change in p53 expression as compared to radiation alone. The regulatory action of melatonin on p53 could be a link between melatonin and its modulatory action on the sensitivity of breast cancer cells to ionizing radiation. These findings may have implications for designing clinical trials using melatonin and radiotherapy.

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients

Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.

Abstract P2-13-26: Trend in primary tumor resection and disease specific survival in patients with metastatic breast cancer: A SEER database analysis (1988-2011)

Abstract INTRODUCTION: The value of primary tumor resection in patients with metastatic breast cancer is a topic of ongoing debate. We aimed to analyze the trend and impact of primary tumor resection on survival over the last two decades using a national database. We hypothesized that there would be a decreasing utilization of primary tumor resection over time with an increase in disease specific survival. METHODS: All patients with stage IV breast cancer at diagnosis between the years 1988 and 2011 were identified in the SEER database. Univariate and multivariate descriptive and survival analyses were performed. RESULTS: A total of 41,601 patients with stage IV breast cancer were included in the study, 98.9 % (41,162) were females and 1.1% were males. Forty percent underwent surgery. Table 1 summarizes the other significant differences in demographic and tumor-related characteristics of patients who did and did not receive PTR. Over the 23- year study period there was a statistically significant temporal trend of decreased primary tumor resection (62% of patients underwent PTR in 1988, 42.4% in 2000 and 27.7% in 2011). On univariate analysis, patients who underwent PTR had a greater median disease-specific survival (DSS), (34 vs. 18 months, p&amp;lt;0.0001). Younger age (p&amp;lt;0.0001), non-African American race (p&amp;lt;0.0001), lower T and N-stage (p&amp;lt;0.0001), positive hormone receptor status (p&amp;lt;0.0001), lower grade (p&amp;lt;0.0001), mucinous histology (p&amp;lt;0.0001), radiation therapy (p&amp;lt;0.0001), and surgery performed in the latter years (p&amp;lt;0.0001) were also associated with improved DSS. On multivariate analysis increasing age (p&amp;lt;0.0001), AA race (p=0.0001), higher T and N stage (p&amp;lt;0.0001), negative hormone receptor status (p&amp;lt;0.0001), higher grade (p&amp;lt;0.0001), no history of radiation therapy (p=0.002), and surgery in earlier years were associated with increased mortality (p&amp;lt;0.0001). Not undergoing PTR was independently associated with increased mortality, (p&amp;lt;0.0001). Table 1: Comparison of patient and tumor characteristics in the surgery vs no surgery group (all p&amp;lt;0.0001)VariableSurgeryNo surgeryFemale (%)16,328 (98.7)24,750 (99.1)White Race (%)13,198 (79.7)19,328 (77.4)T1 stage (%)3,067 (18.5)2,096 (8.4)N1 stage (%)4,173 (25.2)5,834 (23.4)ER Positive (%)9,642 (58.3)12,300 (49.3)PR Positive (%)7,532 (45.5)9,346 (37.4)Her2 Positive (%)414 (4.5)745 (3.0)Grade II (%)4,844 (29.3)5,400 (21.6)Infiltrating ductal cancer (%)11,539 (69.7)12,461 (50.0)Radiation Therapy (%)6,338 (38.3)6,937 (27.8) CONCLUSIONS: Results from this retrospective study suggest a survival advantage in patients with stage IV breast cancer who undergo primary tumor resection. However, there has been a marked reduction in the number of patients undergoing surgery, most likely reflecting more focused patient selection. Ongoing randomized controlled trials will help address the impact of primary tumor surgery on survival of patients diagnosed with metastatic disease. Citation Format: Mahvish Muzaffar, Swapnil D Kachare, Timothy L Fitzgerald, Jan H Wong, Kathryn Verbanac, Nasreen A Vohra. Trend in primary tumor resection and disease specific survival in patients with metastatic breast cancer: A SEER database analysis (1988-2011) [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 P2-13-26.

Abstract P3-12-01: Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide

Abstract Background NSABP B-36 compares 6 cycles of FEC-100 with 4 cycles of standard AC in pts with node-negative breast cancer. As reported separately, no significant differences between the two treatment arms were observed in the primary endpoint of disease-free survival or in the secondary endpoints of overall survival, recurrence-free, or distant recurrence-free intervals. Greater toxicity was reported in pts who received FEC compared to AC. We present here the results of the QOL and MH studies obtained prospectively in conjunction with the treatment study. We hypothesized that pts on FEC would experience greater treatment toxicity in the first 12 months of the study, and would have greater rates of amenorrhea at 18 months compared to pts on AC. Methods Among the 1,357 pts enrolled in the QOL study, 1,332 (675 AC, 657 FEC) submitted the baseline form and had QOL follow-up (fup) information. Pts completed: 1) the FACT-B instrument; 2) a symptom checklist; and 3) the SF-36 Vitality Scale, all at baseline, day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months after random assignment. FACT-B Trial Outcome Index (TOI), symptom severity, and vitality scores were compared between the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, type of surgery, and hormone receptor status, examining the first 12 months and the later time points separately. Menstrual status was collected at baseline for all enrolled pts, with subsequent assessments on day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months for pts with menstrual bleeding within 12 months prior to random assignment and not having had a hysterectomy and/or bilateral oophorectomy (1, 096 pts). Post-chemotherapy amenorrhea was defined as the lack of menstrual periods during the 12 months preceding the 18-month fup evaluation. Data from 921 pts (475 AC, 446 FEC) were available for analysis. Logistic regression, adjusted for type of surgery and hormone receptor status, was used to test for association of amenorrhea status and treatment. Results Both TOI and vitality scores were worse for pts on FEC compared to those on AC at 6 months (p&amp;lt;0.01) with no significant difference at 12 months and beyond. No significant differences in symptom severity between the two treatment arms were observed. The rates of post-chemotherapy amenorrhea were significantly different between FEC and AC (66.8% vs. 58.7%, p=0.01) with positive hormone receptor status as an independent risk factor (p=0.03). Conclusions Women receiving FEC had diminished QOL at 6 months after random assignment, but no difference at 12 months or later. Premenopausal women receiving FEC experienced a higher rate of post-chemotherapy amenorrhea than women receiving AC. Support NCI grants U10-CA-12027, -37377, -69974, -69651 and -44066-26, and Pharmacia &amp; Upjohn Company, a subsidiary of Pfizer, Inc. Citation Format: Patricia A Ganz, John W Wilson, Hanna Bandos, André Robidoux, Alexander HG Paterson, Johnathan Polikoff, Luis Baez-Diaz, Adam M Brufsky, Louis Fehrenbacher, Aroop Mangalik, Patrick J Ward, Louise Provencher, John T Hamm, Philip J Stella, Robert L Carolla, Richard G Margolese, Henry R Shibata, Edith A Perez, Norman Wolmark. Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide [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 P3-12-01.

Abstract P1-04-06: Prevalence of PIK3CA mutations in tumor tissue of a consecutive cohort of breast cancer patients (n=700)

Abstract Introduction: The AKT / mTOR pathway is activated by phosphorylation of the lipid kinase phosphatidylinositol 3-kinase (PI3K) and regulates proliferation, apoptosis, survival and adhesion of tumor cells. In up to 30% of breast cancers, dysregulation of PI3K is reported, resulting from mutations in the PIK3CA gene that encodes the catalytic subunit (p110a). Hotspots of mutations were described in exon 9 (helical domain, E542K, G &amp;gt; A) and exon 20 (kinase domain, H1047R, A &amp;gt; G). Prevalence and the prognostic impact of the PIK3CA mutations as well as the predictive value with regard to endocrine therapy are controversially discussed. In this study we describe the prevalence of PIK3CA mutations in a consecutive cohort of breast cancer patients and its association to tumor characteristics and known prognostic factors. Material &amp; Methods: Fresh frozen tumor samples were obtained from a consecutive cohort of 700 breast cancer patients (inclusion criteria: pTx pNx M0 Gx HRx HER2x) who were primarily operated in 6 centres between 2009 and 2011. Tumor DNA was extracted and analyzed by conventional and quantitative PCR (exon 9: cosmid 763 and exon 20: cosmid 775). Patient data, tumor characteristics and prognostic factors were obtained from patients charts. ER, PgR and HER2 results were based on local pathology, uPA and PAI-1 values were determined centrally. Results: All isolated DNA (n=700) were analyzable by PCR and showed a mutation rate of 22% in the entire cohort; including two tumors with both mutations. Among the tumors with a positive steroid hormone receptor (HR) status (n=606; 87%), we found a mutation rate of 24% for PIK3CA, whereas only 9 (10%) of 94 HR-negative tumors were mutated. Tumors with a PIK3CA mutation were significantly associated with HR positivity / HER2 negativity (p=0,001). 14% of the cohort was HER2 positive. In 98 cases with a HER2 positive tumor 17 DNAs were mutated (17%) and 139 DNAs of the 602 HER2 negative tumors had a positive PIK3Ca mutation status (23%). Of the mutated tumors, 94 % were HR positive, and 11% HER2 positive. Only three samples were HER2 positive and HR-negative. 6% of the mutated tumors were triple negative. No significant association was found to age, menopausal status, tumor stage, nodal status, grading and uPA/PAI-1 status. Most mutant tumors were histological grade 2 (p=0,001). A quarter of the intermediate risk group according to St. Gallen risk estimation had a somatic PIK3CA mutation. Conclusion: In our cohort, nearly all mutated tumors are hormone receptor positive and a minority of all mutated samples is HER2 positive. This data adds important information to the heterogeneous results of other previously published patient cohorts. It suggests a possible role of PI3K-dysregulation with regard to resistance against endocrine therapy and anti-HER2-treatment. Citation Format: Martina Vetter, Kristin Reinhardt, Silke Wegener, Juergen Dittmer, Tilmann Lantzsch, Christoph Uleer, Susanne Peschel, Jutta John, Volker Hanf, Joerg Buchmann, Karl-Friedrich Bürrig, Edith Weigert, Christoph Thomssen, Eva J Kantelhardt. Prevalence of PIK3CA mutations in tumor tissue of a consecutive cohort of breast cancer patients (n=700) [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 P1-04-06.

Prognostic factors in breast cancer with extracranial oligometastases and the appropriate role of radiation therapy

PurposeTo identify prognostic factors for disease progression and survival of patients with extracranial oligometastatic breast cancer (EOMBC), and to investigate the role of radiation therapy (RT) for metastatic lesions.Materials and MethodsWe retrospectively reviewed the medical records of 50 patients who had been diagnosed with EOMBC following standard treatment for primary breast cancer initially, and received RT for metastatic lesions, with or without other systemic therapy between January 2004 and December 2008. EOMBC was defined as breast cancer with five or less metastases involving any organs except the brain. All patients had bone metastasis (BM) and seven patients had pulmonary, hepatic, or lymph node metastasis. Median RT dose applied to metastatic lesions was 30 Gy (range, 20 to 60 Gy).ResultsThe 5-year tumor local control (LC) and 3-year distant progression-free survival (DPFS) rate were 66.1% and 36.8%, respectively. High RT dose (≥50 Gy10) was significantly associated with improved LC. The 5-year overall survival (OS) rate was 49%. Positive hormone receptor status, pathologic nodal stage of primary cancer, solitary BM, and whole-lesion RT (WLRT), defined as RT whose field encompassed entire extent of disease, were associated with better survival. On analysis for subgroup of solitary BM, high RT dose was significantly associated with improved LC and DPFS, shorter metastasis-to-RT interval (≤1 month) with improved DPFS, and WLRT with improved DPFS and OS, respectively.ConclusionHigh-dose RT in solitary BM status and WLRT have the potential to improve the progression-free survival and OS of patients with EOMBC.

Clinical implications of first and multiple locoregional breast cancer recurrences.

Often breast cancer can be treated by breast-conserving surgery (BCS), after which 10 % locoregional recurrences (LRR) occur within 10 years. After BCS mastectomy is recommended at first LRR, although another BCS could be possible. Changes in clinical parameters and in tumor biology from primary breast cancer to first and multiple LRR are described and correlated with further LRR and overall survival (OS). 380 patients with ≥1 ≤3 LRR (1997-2007) were evaluated retrospectively and followed until 5/2009. Patients' age, tumor size, nodal involvement, distant metastases, histological subtype, hormone receptor (HR) and Her-2/neu status were assessed. LRR therapy options were evaluated. 247 patients had one LRR (94 two and 39 three). Mean OS was 10.1 years. Number of LRR was not correlated with OS. Positive HR status was significantly correlated with longer OS. Patients, who changed from primarily ER negative to positive at first LRR had a significantly longer OS compared to those, who remained or changed to ER negative (p < 0.01). Tumor size and grading correlated inversely with OS (both: p < 0.001). BCS at first LRR correlated with a significantly better OS than mastectomy (p < 0.001). LRR cases with chemotherapy had a shorter OS. Irradiation and/or endocrine therapy after LRR were not correlated with OS. Patients with positive HR status had the best survival data. HR should always be determined. In positive cases, endocrine therapy is recommended. As clinical data are good, BCS at first LRR can be suggested for more patients.

Serum HER2 in combination with CA 15-3 as a parameter for prognosis in patients with early breast cancer

AimHER2 in breast cancer tissue is a marker of high prognostic and predictive relevance. Soluble HER2, the extracellular domain of the HER2/neu receptor (HER2 ECD), which is shed into the blood, has been suggested to be a helpful tumor marker. We investigated the relationship between the concentrations of HER2 ECD, CEA and CA 15-3, the association of these markers with clinicopathological features and the impact of HER2 ECD alone and in combination with known prognostic factors on disease free survival (DFS) and cancer specific survival (CSS) in untreated early breast cancer patients. Patients and methodsHER2 ECD (ADVIA, Bayer), CEA (AxSYM, Abbott) and CA 15-3 (Elecsys, Roche) were measured at time of primary diagnosis in the pre-therapeutic (pre-operative) sera of 241 breast cancer patients and were correlated with clinicopathological parameters and outcome. ResultsHigher HER2 ECD levels were significantly correlated with postmenopausal status (p=0.016) and tissue HER2-overexpression (p<0.0001). Higher serum levels of CA 15-3 were associated with larger tumor size (p=0.019), positive lymph nodes (p=0.019), UICC stage III (p<0.01), positive tissue HER2-overexpression (p<0.05) and negative hormone receptor status (p=0.016). In multivariate analysis, serum HER2 ECD levels, CA 15-3 levels, large tumor size and negative hormonal status were independent prognostic factors in DFS. Patients with both high levels of HER2 ECD (>15ng/mL) and high serum levels of CA 15-3 (>24U/mL) had the poorest prognosis with a DFS after 3years of 50.0%. Patients without elevated serum levels had a better outcome with a DFS of 91.2%. ConclusionsIn our retrospective analysis, HER2 ECD and CA 15-3 were independent and better prognostic tools than HER2 in tissue. Prospective validation is necessary to confirm their usefulness in clinical practice.

Optimal surveillance for postoperative metastasis in breast cancer patients.

To establish an optimal surveillance schedule after surgery for breast cancer, patients included in an institutional database were retrospectively investigated with respect to the first metastatic site and timing of recurrence. We investigated 11,676 pT1-4pN0-2M0 breast cancer patients treated from 1985 to 2009 and followed up until June 2014. Our surveillance protocol included physician visits and examinations with bone scans, liver echography, chest roentgenography and laboratory tests. We evaluated the liver, bones, lungs and pleura as surveillance covering sites (SCS) in addition to parameters such as time points exceeding 80 % with respect to the accumulated percentage of patients of recurrence and the number of surveillance per one recurrence (NSR), calculated by dividing the number of patients at risk of recurrence at the start of a particular time frame by the number of patients of recurrence at SCS within that period. There were a total of 1,962 recurrent patients, including 601 patients with locoregional recurrence, nine patients with recurrence in the opposite breast, 1,349 patients with recurrence at distant sites and three unknown patients. The number of patients with the bones, lungs, liver and pleura as the first site of recurrence was 447, 324, 144 and 69, respectively, and 72.9 % of the distant metastatic lesions belonged to SCS. The five-year overall survival rate after recurrence among the patients with single recurrent site was longer than that observed among the patients with multiple sites of recurrence (43.3 vs 25.3 %; p < 0.0001). In addition, more than 80 % of the patients of liver metastasis were detected within 5 years after surgery, while 80 % of the patients of pleura metastasis were detected within 10 years. The NSR was below 200 for the 10-year period, as was the NSR of the patients with lymph node metastasis and a positive hormone receptor status. In contrast, the NSR of the patients with a negative hormone receptor status was above 200 after 5 years. In this study, the prognosis of the patients with a single site of recurrence was superior to that of the patients with multiple sites. Curable patients with distant metastases included those with single metastatic sites. The optimal surveillance schedule should be established taking into consideration that the incidence of metastasis differs among metastatic sites during follow-up.

A retrospective study evaluating a fixed low dose capecitabine monotherapy in women with HER-2 negative metastatic breast cancer.

To determine if a low fixed dosing strategy of capecitabine would produce comparable clinical activity with less adverse toxicities compared to published data with higher doses in the setting of metastatic breast cancer (mBC). We retrospectively analyzed patients treated with a low fixed dose of capecitabine (CAPE-L) at 1,000mg twice daily for 14days every 21days. Outcomes included clinical benefit rate (CBR), overall response rates (ORR), time to progression (TTP), and overall survival (OS). A historical comparison group of mBC patients treated on 12 prior trials at the package-insert dose of capecitabine (n=1,949) was utilized. Eighty-six patients were analyzed in our cohort. Positive hormone receptor status (79.1 vs. 50.6%), and capecitabine as first-line chemotherapy (44.2 vs. 16.5%) were more frequent in our cohort relative to the historical comparison. The median starting dose in our cohort was 633.5mg/m(2). The CBR was similar between the CAPE-L and the standard dose cohorts (55.8 vs. 49.5%), as was ORR (24.3 vs. 24%), and median TTP (7mo, 95% CI 5.5-8.5 vs. 5.1mo, 95% CI 4.5-5.7). Median OS was longer in our cohort (24mo, 95% CI 16.8-31.2) than the historic standard dose cohort (12.1mo, 95% CI 9.6-14.4), a difference that was likely explained by the higher proportion of patients in the CAPE-L cohort who received capecitabine as first-line chemotherapy and who had hormone receptor positive disease. As expected, adverse events were less frequent with CAPE-L. We found that CAPE-L, which translates into a dose of 600-650mg/m(2), appeared to have good clinical efficacy and acceptable toxicity.

Positive expression of insulin-like growth factor-1 receptor is associated with a positive hormone receptor status and a favorable prognosis in breast cancer.

PurposeInsulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined.MethodsIGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive.ResultsPositive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031).ConclusionPositive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.

Complementary or Alternative Medicine as Possible Determinant of Decreased Persistence to Aromatase Inhibitor Therapy among Older Women with Non-Metastatic Breast Cancer

PurposeAromatase inhibitor therapy (AI) significantly improves survival in breast cancer patients. Little is known about adherence and persistence to aromatase inhibitors and about the causes of treatment discontinuation among older women.MethodsWe constituted a cohort of women over 65 receiving a first AI therapy for breast cancer between 2006 and 2008, and followed them until June 2011. Women were selected in the population-based French National Health Insurance databases, and data was collected on the basis of pharmacy refills, medical records and face-to-face interviews. Non-persistence to treatment was defined as the first treatment discontinuation lasting more than 3 consecutive months. Time to treatment discontinuation was studied using survival analysis techniques.ResultsOverall among the 382 selected women, non-persistence to treatment went from 8.7% (95%CI: 6.2–12.1) at 1 year, to 15.6% (95%CI: 12.2–19.8) at 2 years, 20.8% (95%CI: 16.7–25.6) at 3 years, and 24.7% (95%CI: 19.5–31.0) at 4 years. In the multivariate analysis on a sub-sample of 233 women with available data, women using complementary or alternative medicine (CAM) (HR = 3.2; 95%CI: 1.5–6.9) or suffering from comorbidities (HR = 2.2; 95%CI: 1.0–4.8) were more likely to discontinue their treatment, whereas women with polypharmacy (HR = 0.4; 95%CI: 0.2–0.91) were less likely to discontinue. In addition, 13% of the women with positive hormonal receptor status did not fill any prescription for anti-hormonal therapy.ConclusionAI therapy is discontinued prematurely in a substantial portion of older patients. Some patients may use CAM not as a complementary treatment, but as an alternative to conventional medicine. Improving patient-physician communication on the use of CAM may improve hormonal therapy adherence.