Age effect on bone mineral density changes in breast cancer patients receiving anastrozole: results from the ARBI prospective clinical trial

PURPOSE: We investigated whether age at anastrozole (A) initiation influences the effect of treatment on bone mineral density (BMD). We conducted a post hoc analysis of the dataset of Arimidex Bone Mass Index Oral Bisphosphonates prospective trial, studying the effect of risedronate (R) on BMD of postmenopausal, early breast cancer patients receiving A. METHODS: Patients were stratified into those with normal BMD or mild osteopenia (T > −2) receiving A-only and patients with mild or severe osteopenia (T ≤ −2) or osteoporosis (T < −2.5) receiving A and per os R (A + R). Depending on age on treatment initiation, patients were grouped into two age cohorts, above and below 65 years. BMD change in lumbar spine (LS) and hip (HP) was evaluated at 12 months. An analysis of patients with normal BMD at baseline was additionally performed. RESULTS: Among patients receiving A-only, women ≤65 years were more likely to have a decrease in LS-BMD than older (p = 0.034). HP-BMD decrease at 12 months was not related to age (p = 0.182). In patients with mild or severe osteopenia or osteoporosis, treated with A + R, no age effect was observed for LS or HP (p = 0.099 and p = 0.939, respectively). Among patients with normal BMD at baseline, the age effect on LS-BMD change was more profound (p = 0.026). CONCLUSIONS: Our study suggests that younger postmenopausal women with normal BMD or mild osteopenia receiving A-only face an increased risk of bone loss in LS. Among patients with mild or severe osteopenia or osteoporosis treated with A + R, 12 months LS or HP BMD variations were configured regardless of age group

Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

<div><p>Background</p><p><i>HER2</i> and <i>TOP2A</i> gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH). However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17) is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients.</p><p>Methods</p><p>Copy numbers (CN) for 14 genes on chr17, 4 of which were within and 10 outside the core <i>HER2</i> amplicon (HER2- and non-HER2-genes, respectively) were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials.</p><p>Principal Findings</p><p><i>HER2</i>-genes CN strongly correlated to each other (Spearman’s rho >0.6) and were concordant with FISH <i>HER2</i> status (Kappa 0.6697 for <i>ERBB2</i> CN). <i>TOP2A</i> CN were not concordant with <i>TOP2A</i> FISH status (Kappa 0.1154). CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS) and overall survival (OS) in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS). Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS). Non-HER2-gene losses were unfavorable prognosticators in patients with 1–3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS).</p><p>Conclusions</p><p><i>TOP2A</i> FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer patients with known favorable and unfavorable prognosis.</p></div

Multivariate analysis models involving the main significant non-HER2-gene CN pattern effects on patient OS.

<p>Findings as for DFS in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103707#pone-0103707-g006" target="_blank">Figure 6</a>.</p

Significant interactions between non-HER2 gene CN clusters and clinicopathologic parameters affecting patient survival.

<p>In <b>A,</b> among patients with non-TNBC tumors those with non-HER2 gene CN gains fare best; among patients with TNBC, those with non-HER2 gains fare worse. In <b>B,</b> patients with favorable nodal status (1–3 metastatic lymph nodes) and tumors with non-HER2-gene CN losses have similarly bad outcome as those with unfavorable nodal status. In <b>C,</b> non-HER2-gene CN gains strikingly confer the opposite outcome to patients who have undergone modified radical mastectomy (MRM) as compared to breast-conserving surgery (BCS).</p

Hierarchical clustering of log transformed qPCR copy number (CN) values for chr17 genes in association with relevant breast cancer subtypes.

<p><b>A:</b> clustering of all 14 genes was informative in 376 cases and revealed 4 main CN patterns, out of which high CN for the HER2-related genes form the HER2 cluster and are predominantly found in HER2-positive (Luminal-HER2 and HER2-enriched) tumors; gains for the HER2 gene itself (ERBB2) mostly occur in parallel with STARD3. Luminal A and B, as well as TNBC are evenly represented in the non-HER2 clusters. <b>B:</b> If analyzing CN for the 4 HER2-related genes only, 36 of 93 tumors (38.7%) have non-continuous gains for these genes (complex pattern, red cluster) while the rest exhibit continuous gains in at least two genes, predominantly STARD3 and ERBB2 (gains, green cluster). <b>C:</b> Clustering of the non-HER2-related gene CN, i.e., 10 of 14 genes excluding STARD3, ERBB2, PSMD3 and THRA, yields 3 main clusters with equal representation of all subtypes (distribution of HER2-positive tumors and TNBC is shown). Cluster legend: natural log 0.69 corresponds to 2 copies; log 1.38 to 4 copies.</p