Sung Gwe Ahn

Prognostic Factors for Patients with Bone-Only Metastasis in Breast Cancer

Purpose Bone is the most frequent site of metastasis among breast cancer patients. We investigated prognostic factors affecting survival following bone-only metastasis in breast cancer patients. Materials and Methods The medical records of breast cancer patients who were treated and followed at Gangnam Severance Hospital retrospectively reviewed to identify patients with bone-only metastasis. Results The median time from the diagnosis of bone-only metastasis to the last follow-up or death was 55.2 [95% confidence interval (CI), 38.6-71.9] months. The Kaplan-Meier overall survival estimate at 10 years for all patients was 34.9%. In the multivariate Cox regression model, bisphosphonate treatment [hazard ratio=0.18; 95% CI, 0.07-0.43], estrogen receptor positivity (hazard ratio=0.51; 95% CI, 0.28-0.94), and solitary bone metastasis (hazard ratio=0.32; 95% CI, 0.14-0.72) were significantly associated with longer overall survival in the bone-only recurrence group. Among the treatment modalities, only bisphosphonate treatment was identified as a significant prognostic factor. Conclusion Identifying the factors influencing breast cancer mortality after bone-only metastasis will help clarify the clinical course and improve the treatment outcome for patients with breast cancer and bone-only metastasis. Bisphosphonates, as a significant prognostic factor, warrant further investigation.

Molecular Classification of Triple-Negative Breast Cancer

Tumor heterogeneity of triple-negative breast cancer (TNBC) has been the main barrier in conquering breast cancer. To dissect the molecular diversity of TNBC and discover therapeutic targets for TNBC, the molecular classification of TNBC is a prioritized issue in research area. Accordingly, recent studies have been successful in classifying TNBC into several distinct subtypes with specific biologic pathways. Despite the different methodologies used and varied number of final subtypes, these studies identically suggested that TNBC consists of four major subtypes: basal-like, mesenchymal, luminal androgen receptor, and immune-enriched. By reviewing these methods of classifications of TNBC, we highlight the unmet need to develop a molecular classifier suited for TNBC.

Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer

With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

The Difference in Prognostic Factors between Early Recurrence and Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Nodal Stage Differently Impacts Early and Late Recurrence

Background Probability of recurrence in patients with estrogen receptor (ER)-positive breast cancer remains constant for long periods. We compared tumor burden impact on late versus early recurrence in our cohort with long-term follow-up. Methods Five hundred and ninety five patients diagnosed with ER-positive breast cancer between 1989 and 2001 were classified into three groups: early recurrence within 5 years, late recurrence after 5 years, and no recurrence. We identified prognostic factors among the groups using logistic regression analysis. Results At median follow-up of 11.7 years, among 595 ER-positive women, 98 (16.4%) had early recurrence and 58 (9.7%) had late recurrence. On multivariate analysis, higher nodal stage (N0 vs. N2, odds ratio [OR] 3.189; N0 vs. N3, OR 9.948), higher histologic grade (grade 1 vs. grade 2, OR 3.896; grade 1 vs. grade 3, OR 5.945), age >35 years (OR 0.295), and receiving endocrine therapy (OR 0.293) affected early recurrence. Compared to no recurrence, receiving endocrine therapy (OR 0.285) was solely related to decreased risk of late recurrence. Increased risk of early recurrence was noted with the higher nodal stage when early and no recurrences were compared. This phenomenon was not found in late recurrence. In the last comparison between the early and late recurrence, higher nodal stage (N0 vs. N3, OR 16.779) and higher histologic grade (grade 1 vs. grade 3, OR 18.111) repeatedly weighted for early recurrence. Conclusions Nodal burden had an attenuated influence on late recurrence, which suggests that, unlike early recurrence, tumor biology might have a more important role than tumor load for late recurrence in ER-positive disease.

Prognostic discrimination using a 70-gene signature among patients with estrogen receptor-positive breast cancer and an intermediate 21-gene recurrence score.

The Oncotype DX® recurrence score (RS) predictor has been clinically utilized to appropriately select adjuvant chemotherapy for patients with estrogen receptor (ER)-positive early breast cancer. However, the selection of chemotherapy for patients with intermediate RSs remains controversial. We assessed the prognostic value of a 70-gene signature (70GS) among patients with ER-positive breast cancer and intermediate RSs. In addition, we sought to identify genes associated with poor 70GS scores based on gene expression profiling (GEP). GEP was performed using gene expression data from 186 patients with ER-positive breast cancer. The RS and 70GS score were calculated on the basis of GEP. Among 186 patients, 82 ER-positive patients with intermediate RSs were identified. These patients were stratified by 70GS, overall survival (OS) significantly differed according to 70GS (p = 0.013). In a supervised hierarchical analysis according to 70GS, the expression of several representative genes for cell proliferation was significantly higher in the poor 70GS cluster than in the good 70GS cluster. Furthermore, among these patients, FOXM1, AURKA, AURKB, and BIRC5 displayed prognostic significance for OS. In conclusion, 70GS can help to discriminate survival differences among ER-positive patients with intermediate RSs. FOXM1, AURKA, AURKB, and BIRC5, are associated with poor 70GS scores.

Long-Term Survival Analysis of Korean Breast Cancer Patients at a Single Center: Improving Outcome Over Time

Purpose The prognosis of breast cancer has been consistently improving. We analyzed our cohort of breast cancer patients with a long-term follow up at a single center over time. Materials and Methods A total of 1889 patients with known cancer stages were recruited and analyzed between January 1991 and December 2005. Patients were classified according to the time periods (1991-1995; 1996-2000; 2001-2005). To determine intrinsic subtypes, 858 patients whose human epidermal growth receptor-2 status and Ki67 were reported between April 2004 and December 2008 were also analyzed. Results At a median follow up of 9.1 years, the 10-year overall survival (OS) rate was 80.5% for the entire cohort. On multivariate analysis for OS and recurrence-free survival (RFS), the time period was demonstrated to be a significant factor independent of conventional prognostic markers. In the survival analysis performed for each stage (I to III), OS and RFS significantly improved according to the time periods. Adoption of new agents in adjuvant chemotherapy and endocrine therapy was increased according to the elapsed time. In the patients with known subtypes, OS and RFS significantly differed among the subtypes, and the triple-negative subtype showed the worst outcome in stages II and III. Conclusion In the Korean breast cancer cohort with a long-term follow up, our data show an improved prognosis over the past decades, and harbor the contribution of advances in adjuvant treatment. Moreover, we provided new insight regarding comparison of the prognostic impact between the tumor burden and subtypes.

[18F]-fluorodeoxyglucose positron emission tomography can contribute to discriminate patients with poor prognosis in hormone receptor-positive breast cancer.

Background Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can help predict prognosis in patients with hormone receptor-positive breast cancer. Methods Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2) or high Ki67 (≥14%) according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUVmax was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS). Results At a median follow up of 6.23 years, continuous SUVmax was a significant prognostic factor with a hazard ratio (HR) of 1.21 (p = 0.021). The cut-off value of SUVmax was defined as 4. Patients with luminal B subtype (n = 82) or high SUVmax (n = 107) showed a reduced RFS (p = 0.031 and 0.002, respectively). In multivariate analysis for RFS, SUVmax carried independent prognostic significance (p = 0.012) whereas classification with immunohistochemical markers did not (p = 0.274). The Harell c-index was 0.729. High SUVmax was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%), high tumor grade, and luminal B subtype. Conclusions Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.

Metastasis-free interval is closely related to tumor characteristics and has prognostic value in breast cancer patients with distant relapse

Purpose We investigated the relationships between metastasis-free interval (MFI) and tumor characteristics, and assessed the prognostic value of MFI for survival after metastasis in patients with metastatic breast cancer. Furthermore, we compared MFI among the subtypes. Methods We identified 335 patients with postoperative tumor recurrence at distant site(s). All patients underwent curative resection and had a MFI of at least 6 months. MFI was categorized as short (<2 years), intermediate (≥2 years and <5 years), or long (≥5 years). Overall survival after metastasis (OSM) was estimated. Results Patients with a shorter MFI were younger, more likely to have initial metastasis to visceral organs, and had a larger tumor with a higher stage and grade as well as a higher rate of nodal involvement at initial diagnosis. Among 136 patients with known disease subtypes, shorter MFI was associated with the triple-negative subtype while longer MFI was associated with the hormone receptor-positive/human epidermal growth factor receptor 2 negative subtype. Mortality after metastasis declined sharply with increasing MFI up to approximately 2 years, and continued gradually declining between 2 and 5 years. An MFI longer than 5 years did not add any survival benefit. MFI was a significant prognostic factor for OSM independent of nodal status, stage, metastatic site, and hormone receptor status of the metastasized cancer. Conclusion MFI is closely related to biological characteristics of both primary tumors and their metastases, and has a prognostic value for survival after metastasis. We therefore suggest investigation into treatments targeting improvement of MFI as a potential novel strategy.

A survival benefit of major hepatectomy for hepatocellular carcinoma identified by preoperative [18F] fluorodeoxyglucose positron emission tomography in patients with well-preserved hepatic function

AIMS Hepatic resection can cure hepatocellular carcinoma (HCC). However, the optimal extent of resection remains controversial. Major hepatectomy could minimize a tumor recurrence, but it is harmful due to decreased hepatic functional reserve. [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) scans are known as their reflection tumor differentiation and biological activity in HCC. To evaluate a benefit of major hepatectomy for HCC, we performed this retrospective analysis in patients with well-preserved hepatic function, and further analyzed in the subset identified by preoperative FDG-PET. METHODS We reviewed the medical records of 189 patients with HCC who underwent curative resection between August 2004 and December 2010 at two institutes. All patients underwent anatomical resection, either by major or minor hepatectomy. RESULTS Median overall survival did not differ significantly between the major and minor hepatectomy groups (29.4 versus 26.3 months, p = 0.269). However, the major hepatectomy group had a better recurrence-free survival (24.5 versus 19.9 months, p = 0.004). On multivariate analysis, the presence of intrahepatic metastasis independently predicted overall survival (p = 0.009), but other examined variables did not. Overall survival and recurrence-free survival were significantly better following major hepatectomy rather than minor hepatectomy in patients whose preoperative FDG-PET indicated that the maximum standardized uptake value of the tumor (SUVtumor) was ≥4 and the tumor-to-nontumor SUV ratio (TNR) was ≥1.5. CONCLUSIONS Our findings suggest that preoperative FDG-PET may be useful in identifying patients with favorable hepatic reserve who are most likely to benefit from major rather than minor hepatectomy.

The Prognostic Impact of Early Change in 18F-FDG PET SUV After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer

SUV, which is an indicator of the degree of glucose uptake in 18F-FDG PET, can be applied as a prognostic factor in various malignant tumors. We investigated the prognostic impact of early changes in 18F-FDG PET uptake in patients with locally advanced breast cancer who received neoadjuvant chemotherapy. Methods: We retrospectively identified 87 patients who were treated with neoadjuvant chemotherapy followed by surgery for locally advanced breast cancer. All patients underwent 18F-FDG PET at baseline and after 3 cycles of neoadjuvant chemotherapy, and the SUVmax of the primary tumor was assessed in each scan. Pathologic slides were retrospectively reviewed, and the residual cancer burden (RCB) index was calculated to estimate pathologic response. RCB-0 indicates no residual disease; patients with residual disease were categorized as RCB-1 (minimal residual disease), RCB-2 (moderate residual disease), or RCB-3 (extensive residual disease). Results: There was a negative correlation between reduction in SUVmax and RCB index (r = −0.408; P < 0.001). On multivariate analysis, ΔSUVmax was a significant independent prognostic factor for recurrence-free and overall survival, and the respective adjusted hazard ratios were 0.97 (95% confidence interval, 0.95–0.99; P = 0.001) and 0.97 (95% confidence interval, 0.95–0.99; P = 0.015). When patients were categorized into groups according to pathologic response (RCB index ≤ 1 vs. ≥ 2) and metabolic response (ΔSUVmax ≤ 66.4% vs. > 66.4%), metabolic responders had significantly better recurrence-free and overall survival than metabolic nonresponders among poor-pathologic-response patients. In contrast, among metabolic responders, there was no survival difference according to pathologic response. Conclusion: The early change in 18F-FDG PET SUVmax after third-cycle neoadjuvant chemotherapy is an independent and good prognostic marker beyond pathologic response in patients with locally advanced breast cancer. We suggest that in these patients, the use of ΔSUVmax should be considered not only for the assessment of tumor response but for the prediction of posttreatment outcome.