Luminal A-like Breast Cancer Research Articles

Abstract 3995: Breast cancer molecular subtypes are reflected in circulating microRNA profiles

Abstract Background: Breast cancer is a heterogeneous disease. Triple-negative breast cancer (TNBC) as defined by negativity in estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), has a distinct disease course and response to treatment, compared with ER+ breast cancer. Circulating microRNAs (miRNAs) have been suggested as promising diagnostic and early detection biomarkers for cancer, including breast cancer, as miRNAs can be detected in extra-cellular biofluids at stable levels. However, findings from previous studies of circulating miRNA are inconsistent, which may be in part due to the heterogeneity nature of breast cancer. Methods: To characterize the differential expression pattern of circulating miRNAs in TNBC from ER+ breast cancer, we performed a whole miRNome profiling experiment using Exiqon miRCURY microRNA qRT-PCR Human panels which include 752 miRNAs. Total RNA was extracted from 200ul serum of 27 luminal A-like breast cancer patients (ER+/PR+/HER2-), 18 TNBC, and 31 volunteer controls who did not have breast cancer. After global mean normalization, we used linear models and empirical Bayes methods to examine expression differences across the three groups. Benjamini and Hochberg's false discovery rate method was used to correct for multiple testing. Penalized logistic regression was used to build a profile of miRNAs that can distinguish TNBC from luminal A-like breast cancer. Results: The mean age was similar between the three groups (luminal A-like: 51.1, TNBC: 52.5, and controls: 50.6 years old). A total of 226 miRNAs could be detected in more than half of the samples and were included for further analysis. Of them, 20 miRNAs were differently expressed between luminal A-like and control groups, and 12 were different between TNBC and controls. In the contrast between TNBC and luminal A-like breast cancer, we found 34 miRNAs were significantly different, with the most significant miRNA being miR-423 (p = 8.8e-5). The multivariable logistic regression identified a panel of 7 miRNAs which can distinguish TNBC and luminal A-like tumors. ROC analysis found these 7 miRNAs had good discriminatory power (area under ROC curve = 0.865). Conclusion: Our study demonstrates the existence of a set of circulating miRNAs specific to TNBC, which has a clear “fingerprint” to differentiate TNBC from luminal A-like breast cancer. This finding suggests that early detection markers for different breast cancer subtypes may be distinct. It is also interesting to further investigate if different miRNA profiles in circulation between breast cancer subtypes are derived directly from tumors or from other sources in response to tumors. Citation Format: Dezheng Huo, Wendy M. Clayton, Toshio F. Yoshimatsu, Jianjun Chen, Olufunmilayo I. Olopade. Breast cancer molecular subtypes are reflected in circulating microRNA profiles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3995. doi:10.1158/1538-7445.AM2015-3995

Abstract 872: Long-term and recent recreational physical activity reduces risk of triple negative and other subtypes of invasive breast cancer in the California Teachers Study

Abstract Background. Evidence has accumulated showing that physical activity reduces breast cancer risk. Whether risk reduction pertains to all breast cancer or specific receptor-defined subtypes is unclear. Moreover, few studies have examined whether changes in the amount of physical activity during adulthood influence breast cancer risk. Methods. Among 108,907 women, ages 22 to 79 years with no history of breast cancer when they joined the California Teachers Study in 1995-1996 (baseline), 5,578 women were diagnosed with invasive breast cancer during follow-up through December, 2011. Subtypes were defined by the expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Cox proportional hazards models were fit to data to estimate adjusted hazard rate ratios (HRs) and 95% confidence intervals (CIs) associated with long-term and recent (within 3 years of baseline) recreational physical activity. Among 54,690 women who provided updated information on physical activity in 2005-2008, we also assessed whether changes in the level of physical activity since baseline influenced breast cancer risk (654 cases diagnosed during follow-up). Results. Long-term and recent recreational physical activity were inversely associated with risk of triple negative breast cancer (TNBC, both Ptrend ≤ 0.05), but not other subtypes (all Ptrend ≥ 0.07). The reduced risk of TNBC was limited to strenuous physical activity. A 50% (HR = 0.50, 95% CI = 0.29-0.86) lower risk of TNBC was observed among women in the highest (≥5.01 h/wk) versus lowest category (≤0.50 h/wk) of long-term strenuous recreational physical activity; this was not modified by baseline body mass index (<25 kg/m2 vs. ≥25 kg/m2), menopausal hormone therapy (MHT) use (never vs. ever), or the cessation of MHT use (former vs. recent). An inverse association between strenuous recreational physical activity and risk of luminal A-like (ER+ or PR+ plus HER2-) breast cancer was observed only among former MHT users (Ptrend: 0.02 for both long-term and baseline strenuous physical activity). Women who increased their level of recent recreational physical activity from ≤0.50 h/wk at baseline to ≥4.51 h/wk in 2005-2008 had a 32% (HR = 0.68, 95% CI = 0.47-0.99) lower risk of breast cancer overall than those who stayed at the lowest level. Conclusions. This study suggests that long-term strenuous physical activity is associated with lower risk of TNBC. Further, it shows that substantially increasing the amount of total recreational physical activity in adulthood decreases the risk of breast cancer. Citation Format: Huiyan Ma, Jessica Clague, Xinxin Xu, Yani Lu, Kayo Togawa, Sophia S. Wang, Christina A. Clarke, Eunjung Lee, Hannah L. Park, Jane Sullivan-Halley, Susan Neuhausen, Leslie Bernstein. Long-term and recent recreational physical activity reduces risk of triple negative and other subtypes of invasive breast cancer in the California Teachers Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 872. doi:10.1158/1538-7445.AM2015-872

Abstract P6-08-43: Histological grade provides significant prognostic information in the discrimination between luminal A-like and luminal B-like HER-2 normal subtypes of breast cancer according to St Gallen 2013

Abstract Objective: According to St Gallen recommendations from 2013, estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67 defines two subtypes of ER-positive and HER-2 normal breast cancer (BC): Luminal A-like and Luminal B-like. Patients with Luminal B-like BC are often recommended chemotherapy in addition to endocrine therapy, whereas endocrine therapy may be sufficient for patients with Luminal A-like BC. Histological grade (G) 1, 2 and 3 are not included in the St Gallen recommendations. Our unpublished data from a series of 161 premenopausal N0 BC patients with long-term follow-up show that the classification of Luminal A-like vs Luminal B-like HER-2 normal BC is strongly associated to G. Luminal A-like BC is often G1 or G2 and Luminal B-like BC is usually G2 or G3. We also found that the few G3 (n=6) Luminal A-like cases had a prognosis more similar to Luminal B-like and that the few G1 (n=2) Luminal B-like HER-2 normal cases had a prognosis more similar to Luminal A-like. The aim of this study is to evaluate in other cohorts if these findings can be confirmed. Methods: G and St Gallen subtypes were evaluated in three BC cohorts from altogether 547 pre- and postmenopausal chemotherapy naïve T1-2N0-N1M0 patients. The endpoint was distant disease-free survival with 10 years of follow-up. We compared the Luminal A-like and the Luminal B-like HER-2 normal subtype definition according to the original St Gallen recommendation from 2013 based on ER, PR, HER-2 and Ki-67 (St Gallen 2013) with our proposal, where ER-positive, HER-2 normal, G1 BC is defined as Luminal A-like, independent of Ki-67 and PR, and ER-positive, G3 BC is defined as Luminal B-like, independent of Ki-67 and PR (St Gallen 2013+G). The importance of Ki-67 and PR for subtyping was thus restricted to G2 BC. Results: The hazard ratio (HR) between Luminal B-like HER-2 normal (n=185) and Luminal A-like (n=362) defined according to St Gallen 2013+G, was 2.3 (95% confidence interval (CI) 1.6-3.4; p<0.0001) compared to 1.6 (95% CI: 1.1-2.4; p=0.025) according to St Gallen 2013. Twenty-five patients, classified as Luminal B-like HER-2 normal with St Gallen 2013 were G1 and consequently reclassified as Luminal A-like with St Gallen 2013+G. None of these twenty-five patients developed metastases during the follow-up period. Thirty-eight patients showed the opposite pattern (G3 Luminal A-like with St Gallen but Luminal B-like according to St Gallen 2013+G). Seventeen of these patients developed distant metastases already during the first five years. Conclusion: Our findings strongly suggest that ER-positive, HER-2 normal, and G1 BC is a good prognosis group, independent of Ki-67 and PR, and should be treated as Luminal A-like BC, whereas ER-positive, HER-2 normal, and G3 BC should be considered as a worse prognosis group, independent of Ki-67 and PR, and should be treated as Luminal B-like BC. Based on our findings the importance of Ki-67 and PR is restricted to G2 BC for the discrimination between Luminal A-like and Luminal B-like HER-2 normal subtypes of BC. Citation Format: Anna Ehinger, Per Malmström, Pär-Ola Bendahl, Christopher W Elston, Anna-Karin Falck, Carina Forsare, Dorthe Grabau, Lisa Rydén, Olle Stål, Mårten Fernö. Histological grade provides significant prognostic information in the discrimination between luminal A-like and luminal B-like HER-2 normal subtypes of breast cancer according to St Gallen 2013 [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 P6-08-43.

Prognostic significance of the progesterone receptor status in Ki67-high and -low Luminal B-like HER2-negative breast cancers.

Breast cancer is a heterogeneous disease, and immunohistochemical evaluation is a surrogate marker that is widely used in clinical settings to identify the intrinsic subtypes. The definition of the Luminal B-like breast cancer was changed at the 2013 St. Gallen meeting; therefore, we investigated the clinicopathological features of the new Luminal B-like breast cancer categorized in the latest definition. We also compared the conventional PgR-high Luminal B-like breast cancer with the conventional PgR-low or -negative Luminal B-like breast cancer. We investigated 118 Luminal HER2-negative breast cancer patients who were operated in 2005-2008 at a single institution. Data on each patient's medical history were retrieved. A subset of patients (14.4 %) was categorized as the new Luminal B-like due to low or negative PgR: 58.8 % were histological grade I, 65 % were T1 in tumor size, and half had node involvement. Chemotherapy was performed in half of the cases. Breast cancer-related events were more frequent for the new Luminal B-like breast cancer than for the Luminal A-like breast cancer and were less frequent than for the conventional Luminal B-like breast cancer. Based on multivariate analysis, low or negative expression of PgR and the absence of hormonal therapy were worse prognostic factors. When categorized into two groups by the PgR status, 48.1 % of the conventional Luminal B-like breast cancer was PgR-high; tumor size was smaller, and nodal involvement was less in this group. The rate of adjuvant chemotherapy of the conventional PgR-high Luminal B-like breast cancer was less than that of the conventional PgR-low or -negative Luminal B-like breast cancer. Breast cancer-related events were significantly lower in the conventional PgR-high Luminal B-like breast cancer. Our results show the possibility that PgR status has some influence on the prognosis for Luminal HER2-negative breast cancers. Therefore, attention should be paid to the PgR status as well as Ki-67.

Abstract 1083: Host-tumor immune response for early breast cancer patients treated with radiofrequency ablation therapy

Abstract [Background] We demonstrated immune suppression of regulatory T (Treg) cells in preoperative breast cancer (BC) patients at AACR 2011. Last year we also reported at this meeting that Th17 cells might have some potential to control tumor progression in the same cohort. Modern treatment of operable BC consists of breast surgery, drug therapy and radiation therapy. [Aim] To explore new strategy of BC treatment, we conducted a phase II study on radiofrequency ablation (RFA) in early BC between 2009 and 2013. Twenty patients were enrolled. To examine host-tumor immune response under thermal ablation therapy, Treg cells in peripheral blood mononuclear cells (PBMC) and plasma IL-17A were measured. [Patients and methods] Blood samples were collected from 13 patients before RFA and at the time of 1 month after RFA. Treg cells were examined by counting CD4+CD25highCD127low/-cells in PBMC. Plasma IL-17A was measured using cytometric beads array system. Statistical significance was analyzed using Mann-Whitney U-test. [Results] As of November 2013, all patients were free of recurrence. The percentages of Treg cells had no significant change in 13 patients before and after RFA (2.8% versus 2.7% of CD4-positive cells at mean value). In addition, there was no statistical difference in levels of plasma IL-17A before and after RFA (76 pg/ml versus 116 pg/ml at mean level). [Discussion] Unexpectedly, RFA had no favorable immune response in BC patients, because we observed significant decrease in percentages of Treg cells after breast surgery. The reason is that most patients had T1 tumor and Luminal A-like BC. They had lower percentages of Treg cells in comparison to those of tumor-bearing patients reported previously (2.8% versus 4.2%). [Conclusion] RFA is a promising alternative to breast surgery. However, it may make little effect on host-tumor immune response in favorable subtype of early BC. Citation Format: Shigeru Imoto, Noriko Nakatsugawa, Takayuki Ueno, Hiroki Ito, Kentaro Imi, Kaisuke Miyamoto, Manami Kitamura, Hirotsugu Isaka, Tetsuya Nakatsura. Host-tumor immune response for early breast cancer patients treated with radiofrequency ablation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1083. doi:10.1158/1538-7445.AM2014-1083

Prognostic score for Luminal A-like breast cancer patients.

525 Background: Luminal A breast cancer (BC) is considered a subtype with a good prognosis, but some poor prognostic factors can be identified, i.e. advanced stage and/or young age at presentation ...

Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer.

IntroductionBreast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting.MethodsBlood samples were prospectively collected from patients with Luminal A-like breast cancer (n = 54) and controls (n = 56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n = 10 Luminal A-like; n = 10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n = 44 Luminal A; n = 46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated.ResultsMicroarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis (miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652). The biomarker potential of 4 miRNAs (miR-29a, miR-181a, miR-223 and miR-652) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p = 0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs (miR-29a, miR-181a and miR-652) could reliably differentiate between cancers and controls with an AUC of 0.80.ConclusionThis study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype-specific breast tumor detection.