HR-positive Breast Cancer Patients Research Articles

Everolimus in the treatment of hormone receptor-positive breast cancer

Introduction: The phosphoinositide triphosphate kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is a central regulatory pathway involved in cell proliferation, growth, differentiation, metabolism and survival. Deregulation of this pathway is well described in breast cancer and is associated to the development of endocrine resistance among hormone receptor (HR)-positive tumors. Everolimus, an mTOR-inhibitor has clinical activity against breast cancer and has shown to restore sensitivity to endocrine therapy.Areas covered: We review the clinical data and the results of the recently published clinical trials evaluating the use of everolimus in HR-positive breast cancer patients in combination with endocrine therapy. We discuss the data regarding efficacy but also describe in detail the side effect profile of this drug.Expert opinion: Everolimus represents a new therapeutic alternative for the treatment of HR-positive metastatic breast cancer. Everolimus is in general a well-tolerated drug, however, stomatitis, fatigue and hematological abnormalities are common. It is still unclear if there are specific subgroups of patients that receive greater benefit from everolimus and whether there is a relationship between the presence of PIK3CA mutations and efficacy. The results of biomarker studies will hopefully provide information that will help us determine which patients are most likely to benefit from this treatment.

Small node-negative (T1b-cN0) invasive hormone receptor-positive breast cancers: Is there a subpopulation that might have benefit from adjuvant chemotherapy?

The aims of the study were to identify a subpopulation more likely to be at greater risk of recurrence in small T1b-c node-negative hormone receptor (HR)-positive breast cancer, and which would benefit from adjuvant chemotherapy. Clinico-pathologic characteristics and clinical outcomes of 538 postoperative HR-positive T1b-cN0 breast cancer patients were retrospectively analyzed. High Ki67 index and a young age (< 35 years) were identified as independent risk factors for relapse (p < 0.0001 and 0.015, respectively). A nomogram based on Cox-regression model showed an area under the curve (AUC) of 0.73 in the training set. The validation set showed a good discrimination with an AUC of 0.65. In patients with high nomogram scores (≥ 100, n = 24, 4.5%) who had high Ki67 index with more than 75%, or young age (< 35 years) and a Ki67 index > 50%, the relapse-free survival curve of patients who had received anthracycline-containing adjuvant chemotherapy showed a better outcome than those who had not (p = 0.029). Ki67 index and age are valuable surrogate markers to predict recurrence and as indicators of tumors that could benefit from adjuvant chemotherapy in small T1b-c node-negative HR-positive breast cancer.

P5-01-11: Small Node-Negative (T1b-cN0) Invasive Hormone Receptor (HR)-Positive Breast Cancers: Is There a Population Which Might Have Benefit from Adjuvant Chemotherapy?

Abstract Background It has been widely accepted that small and node-negative breast cancers have an excellent prognosis and do not generally have clinical benefit from adjuvant chemotherapy. Recently, the role of adjuvant chemotherapy for small node negative breast cancers has been justified in some high-risk patients, which include HER2−positive and triple negative breast cancers. However, the question has been raised as to whether there are some patients who might have benefit from adjuvant chemotherapy in small node-negative HR-positive breast cancers. According to the current 2011 NCCN guideline, 21-gene RT-PCR assay can be considered for tumor size of more than 0.5 cm in HR-positive, HER2−negative cancers. In cases of high recurrence score (≥ 31), adjuvant chemotherapy in addition to endocrine therapy is recommended as category 2B. Because gene array cannot routinely be used in clinical practice and has not been validated in prospective randomized trials and the usefulness of it still needs to be defined, it would be better if there were valuable markers to determine risk for relapse in this setting. We hypothesized that there could be a population who might have clinical benefit from adjuvant chemotherapy in this small node-negative HR-positive tumors. Patients and Methods We retrospectively analyzed the clinicopathologic characteristics and outcomes of 538 postoperative HR-positive (ER-positive and/or PgR-positive) T1b-cN0 breast cancer patients between 2004 and 2007 at the Samsung Medical Center. We performed Cox regression multivariate analysis for relapse using variables from univariate analysis by log-rank test for relapse. Results: The median age at diagnosis was 46 years (range, 22–79). During the median 60.5 months of follow-up, the 5-year recurrence rate was 5.2%. Anthracycline-based adjuvant chemotherapy was administered to 44.8% of the patients. Adjuvant endocrine and radiation treatment were administered to 94.6% and 63.7% of the patients. There were significant differences according to histologic grade (HG), Ki67 index, and age of less than 35 years in univariate analyses regarding RFS (p=0.003, p&amp;lt;0.0001, and p=0.003, respectively by log-rank test). There was no significant difference according to tumor size of subcentimeter (&amp;lt; 1cm) (p=0.826). In Cox regression multivariate analysis, high Ki67 index and young age of less than 35 years were identified as independent risk factors for relapse (p&amp;lt;0.0001 for Ki67 index and 0.015 for young age). The high risk patients (n=24, 4.5%) who have high Ki67 index (more than 75%, 4+) or young age of less than 35 and more than 50% of Ki67 index showed better RFS with statistical significance for anthracycline-containing adjuvant chemotherapy (p=0.029). Conclusion: A patients’ population may exist who have clinical benefit from adjuvant chemotherapy in T1b-cN0 HR-positive breast cancer patients. Ki67 index and age are useful as valuable surrogate markers to predict recurrence and to have benefit from adjuvant chemotherapy in this population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-11.

P5-14-15: Prognostic Impact of Chemotherapy-Induced Amenorrhea (CIA) in Premenopausal Breast Cancer: A Meta-Analysis of Published Literatures.

Abstract Background: Various studies have reported inconsistent results on the prognostic effect of chemotherapy-induced amenorrhea (CIA) in premenopausal breast cancer. Therefore, we conducted a meta-analysis to assess the effect of CIA on prognosis of premenopausal women with breast cancer. Methods: The PubMed database was searched for all relevant studies published before March 2011. Relative risks (RRs) were used to estimate the association between CIA on various survival outcomes. Subgroup analyses were also performed by age, nodal status and hormone receptor (HR) status. Results: With thirteen eligible studies identified, this meta-analysis included 5790 cases and 2159 controls. This meta-analysis demonstrated that CIA was associated with improved DFS (RR= 0.39, 95%CI: 0.32∼0.47, p&amp;lt;0.001) and OS (RR= 0.30, 95%CI: 0.21∼0.44, p&amp;lt;0.001). In the subgroup analyses, the effect of CIA on DFS and OS also existed in HR-positive subjects (for OS, RR= 0.19, 95%CI: 0.07∼0.49, p=0.001; for DFS, RR= 0.47, 95%CI: 0.35∼0.63, p&amp;lt;0.001) while similar results failed to be observed in HR-negative patients (for OS, RR= 0.62, 95%CI: 0.07∼5.75, p=0.671; for DFS, RR= 1.48, 95%CI: 0.50∼4.37, p=0.474). Furthermore, significant difference was achieved between women with and without CIA, irrespective of age and nodal status.*** Conclusion: This meta-analysis clarifies that CIA might contribute to the improvement of prognosis in HR-positive premenopausal breast cancer patients, which is at least partially responsible for the benefit of adjuvant chemotherapy in premenopausal women through chemical castration. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-15.

P2-12-19: Nomogram To Predict Recurrence and To Avoid Unnecessary Adjuvant Chemotherapy Based on Ki67 Index and ER Status in Hormone Receptor (HR)-Positive Breast Cancers with Low Number of Nodal Metastases (≤3) (NCT01273415).

Abstract Background Hormone receptor (HR) positive breast cancers characterized with ER-associated genes are differentiated luminal B from luminal A tumors mainly by proliferation genes. According to NCCN guideline 2011, node positivity has been a main determinant to decide adjuvant chemotherapy with category 1. However, the experts’ panel at the St. Gallen Consensus in 2009 do not provides definite indications to give or withhold chemotherapy in patient group with intermediate criteria including low numbers (1-3, N1) of involved lymph nodes. Thus, in cases of limited number of nodal metastases, the role of biologic factors including Ki67 index needs to be defined. The aims of this study are to evaluate of Ki67 index as a useful surrogate marker to predict recurrence and to avoid unnecessary adjuvant chemotherapy and to develop nomogram based on Ki67 index to determine adjuvant therapeutic options in HR-positive in N0 and N1 breast cancers. Patients and Methods We retrospectively analyzed the clinicopathologic characteristics and outcomes of 953 postoperative HR-positive N0 and N1 breast cancer patients between 2004 and 2007 at the Samsung Medical Center. We constructed nomogram based on Cox regression model using independent factors demonstrated in multivariate analysis and validated externally in a cohort of 895 patients treated at Seoul National University Hospital. Results: In Cox regression multivariate analysis, ER-ve/PgR+ve and Ki67 index were identified as independent factors. Nomogram base on Cox-regression model showed an AUC of 0.75 (95% CI, 0.72−0.77) in the training set. The validation set showed a good discrimination with an AUC of 0.63 (95% CI, 0.60−0.66). We defined low nomogram score as less than 53, and high nomogram score as 53 or more from the cut-off value of the nomogrma ROC curve. Patients who received anthracycline-containing adjuvant chemotherapy with high nomogram scores showed better RFS with statistical significance than those who did not receive anthracycline-containing adjuvant chemotherapy with high nomogram scores (p&amp;lt;0.0001). In contrast, the patients with low nomogram scores did not show any benefit from anthracycline-containing adjuvant chemotherapy (p=0.804). When the patients with high nomogram scores divided into two groups according to Allred ER scores (0-4 vs 5–8), the patients with high ER Allred scores (5-8) and high nomogram scores did not show any benefit from anthracycline-containing chemotherapy (p=0.283). Main benefit from adjuvant chemotherapy is focused on the patients with low ER Allred scores (0-4) and high nomogram score (p=0.022). Conclusion: Ki67 index is useful as a valuable surrogate marker to predict recurrence and to avoid unnecessary chemotherapy. Nomogram based on Ki67 index is constructed and validated to determine adjuvant therapeutic options in HR-positive N0 and N1 breast cancers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-19.

Abstract P4-08-07: Correlation of Oncotype Dx Recurrence Score and Luminal Subtypes of Breast Cancer

Abstract Background: Molecular subtypes of breast cancer have been characterized by gene expression analysis. Luminal subtypes are hormone receptor (HR) positive and Her2/neu negative. Immunohistochemistry (IHC) has been used as a surrogate test for gene expression. Ki67 is a proliferation marker that identifies high-risk subtype of luminal breast cancer. Recently, the proposed Ki67 index (KI) of 14% was suggested as a cut-off to distinguish between luminal A and luminal B tumors (JNCI. 2009;101:736-750). The oncotype dx (ODx) is a 21- gene test that provides prognostic and predictive information in early stage HR-positive breast cancer patients. The test is reported as low (&amp;lt;18), intermediate (18-30) and high (&amp;gt;30) risk recurrence scores (RS) Design: We investigated the relationship between ODx RS and luminal subtypes of breast cancers using the KI of 14% as the cut-off for distinguishing luminal A and B tumors. Biomarker analysis (ER, PR, Her2/neu, Ki67 and p53) was performed as part of the diagnostic work-up using standard IHC procedures. Scoring was done by automated image analysis. Her2/neu FISH was performed on all IHC 2+ and 3 + results. Pathologic parameters such as, tumor size, grade, and presence of LVI were evaluated. Ploidy was performed by the Autocyte system (Tripath) on Feulgen stained paraffin sections. Results: We identified 106 patients with HR positive breast cancer who were tested for ODx from February 2006 to May 2010. 85/106 had Ki67 data available for analysis. 46/85 (54%) were luminal A and 39/85 (46%) luminal B tumors. The mean KI in luminal A was 6.93% versus 31.1% in luminal B (P&amp;lt;0.0001). The mean tumor size was 1.94 and 1.92 cm in luminal A and B respectively. Grade 1, 2 and 3 comprised 28/85 (32.9%), 49 (57.6%) and 8 (9.41%) of all tumors respectively. Of the grade1 tumors, 75% were luminal A, and grade 3 tumors were predominantly luminal B (p=0.013). LVI was present in 16 cases, 11 (68.8%) in luminal B and 5/16 (31.2%) in luminal A tumors (p=0.0416). Luminal A tumors were predominantly diploid 30/45 (66.6%) and luminal B were mostly aneuploid 21/32 (65.6%) (p=0.019). The overall mean RS in luminal A and B tumors was 14.67 and 20.15 respectively (P&amp;lt;0.0004). Luminal A tumors had low RS in 32/46 (66.6%). and luminal B tumors had predominantly intermediate/high RS in 23/39 (62.1%) (p=0.0082). ER Allred Scores were 7.1 and 7.3 and percent positivity was 88.1% and 91% respectively for luminal A and B subtypes. PR Allred scores were 5.6 and 5.8, and percent positivity was 62.1 and 52.9% for A and B tumors respectively. Information regarding treatment was available in 72 cases. 19 (26.3%) were treated by a combination of chemo and anti-hormonal therapy and 53 (73.6%) were treated by anti hormonal therapy alone, 8 of the 19 (42.1%) luminal A patients received combination therapy versus 11 (57.8%) in the luminal B category (p=0.277). Conclusion: Ki67 is a useful marker that showed significant correlation with RS by ODx. Luminal A tumors are more likely to be low grade, diploid with low RS compared to luminal B tumors. Ki67 in conjunction with other pathologic parameters may serve as a surrogate marker for the ODx RS. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-07.

New trends in primary systemic therapy for breast cancer

Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced breast cancer. NAC is also recognized as the initial treatment of choice for patients who are candidates for adjuvant chemotherapy. A pathologic complete response (pCR) is a predictor of outcome associated with improved disease-free and overall survival. The identification of accurate predictors of a pCR to NAC is important to spare patients unnecessary toxicity. Hormone receptors, histologic grade, HER2, and ki-67 labeling index were evaluated as predictors of a pCR. An early response to NAC might be correlated with a high probability of a pCR. Jinno et al. reviewed indications for and predictors of NAC. The histological effects differ among the subtypes of breast cancer when the same NAC regimen is administered. In clinical studies of patients with HER2positive breast cancer, NAC with trastuzumab resulted in high pCR rates. The induction of personalized medicine and new molecular targeted therapies are expected to result in higher pCR rates in NAC. Dr Kinoshita summarized the current consensus on the adoption and benefits of NAC, especially for operable breast cancer patients. Hormone receptor (HR)-positive, HER2-negative breast cancer is regarded as a subtype with a good prognosis and which is sensitive to hormone therapy. Endocrine therapy may be sufficient for some HR-positive, HER2-negative breast cancer patients. Neoadjuvant endocrine therapy (NAE) is a new treatment option for such patients. Takei et al. reviewed NAE for premenopausal breast cancer patients using a luteinizing hormone-releasing hormone (LH-RH) analogue plus tamoxifen and for postmenopausal breast cancer patients using tamoxifen or aromatase inhibitors. The prognosis of HR-positive breast cancer patients receiving NAE has not been evaluated thoroughly. No comparative study of pre and postoperative endocrine therapy is available. Dr Iwata has introduced a new clinical study, N-SAS BC06, which is a randomized phase III trial conducted in Japan. Postmenopausal women with ER-positive, HER2-negative T1c-T2 N0 M0 breast cancer were classified into complete response (CR), partial response (PR), or stable disease (SD) groups and the progressive disease (PD) group, and patients in the CR, PR, or SD groups were randomized to a chemotherapy followed by endocrine therapy group or to an endocrine therapy group. The primary endpoint is disease-free survival. Immunohistochemical (IHC) biomarkers such as ER, PgR, and HER2 are very important predictors of the sensitivity to endocrine therapy or chemotherapy. Recently, there has been a focus on IHC evaluation of Ki-67 as a predictor of breast cancer outcome. Kumaki et al. reviewed our present understanding of the IHC evaluation of biomarkers for breast cancer under NAC.

Anastrozol (Ana) versus tamoxifen (Tam) treatment in postmenopausal breast cancer women with tamoxifen treatment and abnormal vaginal bleeding: Results from an open-label randomized trial

648 Purpose: To compare the effects of switching from adjuvant Tam treatment to Ana in postmenopausal breast cancer women with abnormal vaginal bleedings during Tam treatment and histologically proven benign endometrial pathology. Patients & Methods: 110 postmenopausal women who had received Tam 20 mg/day (312 months, £48 months) and developed abnormal vaginal bleeding were subjected to hysteroscopy as well as dilation and curettage (D&C). Thereafter they were randomized to continue Tam treatment (n=88) or switch to Ana 1 mg/day (n=83). Patients were monitored for £42 months using transvaginal ultrasound (TVUS) at 6 monthly intervals. Results: At the time of study entry, there was no significant difference between vaginal bleeding, endometrial thickness and histological findings between the two treatment groups. Six months after randomization, the mean endometrial thickness in patients who switched to Ana was significantly reduced compared with those who continued Tam treatment (p<0.0001). This significant difference was sustained throughout the treatment period. There was a significant difference in recurrent vaginal bleeding (Tam: 32%, 17/53 and Ana: 4/57, 7% respectively; p<0.0001). In consequence patients receiving anastrozole required fewer repeat hysteroscopy and D&C compared with those who continued Tam treatment. Repeat hysteroscopy and D&C revealed endometrial atrophy in all four cases in the Ana group and 10 polyps, 6 hyperplasias and one endometrial cancer in the Tam group. The first and second histological findings were consistent in 12 (71%) of the 17 patients assessed (p=0.001). Conclusions: Anastrozole represents an effective treatment for the prevention of repeated endometrial pathology in postmenopausal HR-positive breast cancer patients with Tam-induced abnormal vaginal bleedings. No significant financial relationships to disclose.

MRNA expression level of estrogen‐inducible gene, α1‐antichymotrypsin, is a predictor of early tumor recurrence in patients with invasive breast cancers

We previously identified 18 genes that correlated with ER positivity by adapter-tagged competitive-PCR analysis of 2412 genes in human breast cancer tissues. The aim of the present study was to determine the prognostic significance of these genes. mRNA expression levels of 12 of the above 18 genes were quantified in breast cancer tissues by real-time PCR assay, and their association with patients' prognosis (n = 110) was studied according to hormone receptor (HR) status. In addition, the genes found to influence prognosis were further investigated to examine whether their mRNA expression could be induced by estrogen in MCF-7 cells in vitro. Of the 12 genes, mRNA expression levels of two [alpha 1-antichymotrypsin (ACT) and stanniocalcin 2 (STC2)] were significantly (P = 0.002 and P = 0.007, respectively) associated with good prognosis in HR-positive (ER and/or PR positive) breast cancer patients treated with adjuvant hormone therapy. Multivariate analysis showed that ACT mRNA level, but not STC2 mRNA level, in HR-positive patients, was a significant prognostic factor (P = 0.042), which was independent of tumor size and lymph node metastases. On the other hand, mRNA expressions of ACT and STC2 were not significantly associated with prognosis in HR-negative patients. Estradiol treatment resulted in a significant increase in the mRNA levels of both ACT and STC2 in MCF-7 cells. The mRNA level of ACT, which is an estrogen-inducible gene, is a significant predictor of good prognosis in HR-positive, but not HR-negative, patients with breast cancers. Since HR-positive patients were treated with adjuvant hormone therapy, we suggest that ACT mRNA level could potentially be used as a predictor of response to hormone therapy, rather than a prognostic factor (predictor of metastatic potential).