Hak Woo Lee

Standardized uptake value of 18F-fluorodeoxyglucose positron emission tomography for prediction of tumor recurrence in breast cancer beyond tumor burden

Introduction18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can reveal the metabolic activity of malignant tumors. Recent advances gained from molecular studies suggest that tumor biology can be a good predictor of prognosis in breast cancer. We compared the ability of maximum standardized uptake values (SUVmax) derived by FDG-PET with tumor burden in predicting tumor recurrence for patients with breast cancer.Methods496 patients with breast cancer who underwent preoperative FDG-PET between April 2004 and May 2009 were retrospectively identified. SUVmax was obtained by FDG-PET, and the cutoff point was defined using a time-dependent receiver operating characteristic curve for recurrence-free survival (RFS). The primary endpoint was RFS.ResultsIn multivariate analysis for RFS, SUVmax carried independent prognostic significance (hazard ratio, 2.39; 95% confidence interval, 1.20 to 4.76; P = 0.012). When the patients were classified into four groups according to the combined factors of tumor size (≤2 cm versus >2 cm) and SUVmax (<4 versus ≥4), RFS differed significantly (P < 0.001). Similarly, SUVmax had prognostic value in combination with nodal status (negative versus positive) or stage (I versus II and III) (P < 0.001 and P = 0.001, respectively). In hormone receptor–positive disease, SUVmax remained a significant prognostic factor for RFS based on multivariate analysis.ConclusionsOur results highlight the prognostic value of FDG-PET in prediction of tumor relapse for patients with breast cancer. Particularly in patients with hormone receptor–positive disease, the tumor metabolic information provided by FDG-PET is more significantly correlated with prognosis than tumor burden.

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.

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.

Clinical Implications of Microsatellite Instability in T1 Colorectal Cancer

Purpose The estimation of regional lymph node metastasis (LNM) risk in T1 colorectal cancer is based on histologic examination and imaging of the primary tumor. High-frequency microsatellite instability (MSI-H) is likely to decrease the possibility of metastasis to either regional lymph nodes or distant organs in colorectal cancers. This study evaluated the clinical implications of MSI in T1 colorectal cancer with emphasis on the usefulness of MSI as a predictive factor for regional LNM. Materials and Methods A total of 133 patients who underwent radical resection for T1 colorectal cancer were included. Genomic DNA was extracted from normal and tumor tissues and amplified by polymerase chain reaction (PCR). Five microsatellite markers, BAT-25, BAT-26, D2S123, D5S346, and D17S250, were used. MSI and clinicopathological parameters were evaluated as potential predictors of LNM using univariate and multivariate analyses. Results Among 133 T1 colorectal cancer patients, MSI-H, low-frequency microsatellite instability (MSI-L), and microsatellite stable (MSS) colorectal cancers accounted for 7.5%, 6%, and 86.5%, respectively. MSI-H tumors showed a female predominance, a proximal location and more retrieved lymph nodes. Twenty-two patients (16.5%) had regional LNM. Lymphovascular invasion and depth of invasion were significantly associated with LNM. There was no LNM in 10 MSI-H patients; however, MSI status was not significantly correlated with LNM. Disease-free survival did not differ between patients with MSI-H and those with MSI-L/MSS. Conclusion MSI status could serve as a negative predictive factor in estimating LNM in T1 colorectal cancer, given that LNM was not detected in MSI-H patients. However, validation of our result in a different cohort is necessary.

In Vitro Chemoresponse Assay Based on the Intrinsic Subtypes in Breast Cancer

OBJECTIVE In vitro chemotherapy response assays are not widely accepted in making decisions regarding cytotoxic drugs. To evaluate the usefulness of chemotherapy response assays in breast cancer, we compared the chemotherapy response assay results according to subtypes. Human epidermal growth factor receptor-2 and Ki67 associated with chemosensitivity were also analyzed. METHODS Four hundred and ninety-six patients were enrolled, and chemotherapy response assays based on adenosine triphosphate were performed in 500 tumors. Patients were classified as five subtypes: luminal A, luminal B/human epidermal growth factor receptor-2 negative, luminal B/human epidermal growth factor receptor-2 positive, human epidermal growth factor receptor-2 and triple negative. The cell death rate for various drugs was calculated. RESULTS The mean cell death rate of the luminal A subtype was the lowest, and the mean cell death rates of the human epidermal growth factor receptor-2 and triple-negative subtypes were the highest for all tested drugs, except 5-fluorouracil and methotrexate. The cell death rate differed significantly among the subtypes in the types of drugs (doxorubicin, epirubicin, paclitaxel, docetaxel, gemcitabine, vinorelbine and cisplatin). In triple-negative tumors, the mean cell death rate of cisplatin was the highest among the tested drugs, and which was not observed in the other subtypes. Human epidermal growth factor receptor-2 positive tumors are associated with higher cell death rates for anthracyclines. High Ki67 expression (a cutoff of 14%) was associated with a high response in several tested drugs including epirubicin, paclitaxel, docetaxel, gemcitabine, vinorelbine and cisplatin. CONCLUSIONS Our findings suggest that in vitro chemoresponse assays for breast tumors could effectively reflect the tumor response to chemotherapies observed in neoadjuvant settings.

Assessment of Adjuvant Trastuzumab-Associated Cardiac Toxicity in Korean Patients with Breast Cancer: A Single-Center Analysis

Background: We performed this analysis to investigate the clinical presentation of trastuzumab-associated cardiac toxicity in Korean women. Method: 124 patients treated in a single institute from January 2006 to November 2011 with adjuvant trastuzumab therapy following primary surgery were identified from a database. We evaluated the cumulative incidence of cardiac toxicity, associated risk factors, and changes in cardiac function during trastuzumab treatment. Results: The median age of patients was 50 years (range 27-73). After 12 months of follow-up, the cumulative incidence of cardiac toxicity was 12.1% (grade I: 8.1%, grade II: 0.8%, grade III: 3.2%). In total, 4% of patients discontinued treatment due to cardiac dysfunction. The left ventricular ejection fraction (LVEF) recovered in all patients who discontinued or delayed treatment due to cardiac dysfunction following treatment discontinuation. The degree of the decrease in LVEF was large at 6 months after the initiation of treatment. A lower LVEF at baseline (<65%) was associated with cardiac toxicity. Conclusions: The low incidence of cardiac toxicity and the reversibility of cardiac dysfunction may validate the safety of trastuzumab treatment in Korean women with an acceptable baseline LVEF.

Comparison of standardized uptake value of 18F-FDG-PET-CT with 21-gene recurrence score in estrogen receptor-positive, HER2-negative breast cancer

Background We investigated the relationship between 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT) standardized uptake value (SUV) and 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer. Materials and methods One hundred sixty-seven patients were identified among those who underwent preoperative 18F-FDG-PET-CT and had RS. Maximum SUV was obtained from 18F-FDG-PET-CT; the cut-off point was 4. Results The continuous RS and SUV correlated positively (Pearson’s R = 0.555; P < 0.001). An inverse correlation was found between progesterone receptor (PR) expression by reverse transcriptase-polymerase chain reaction, and SUV (Pearson’s R = -0.408; P < 0.001). Good agreement between dichotomized RS (<26 vs. ≥26) and SUV (<4 vs. ≥4) was observed in 137 of 167 patients (82.0%; 95% confidence interval [CI], 76.2–87.9). Among patients with low SUV, 114 of 115 (99.1% [95% CI, 97.4–100.0]) had tumors with lower RS (<26). Although 23 of 52 women (44.2% [95% CI, 30.7–57.7]) with high SUV had higher RS (≥26), all 13 women with high RS (≥31) had high-SUV tumors. Most cases with disagreements between SUV and RS (n = 30) were classified as high SUV/lower RS (n = 29). The discordant group had higher grade or elevated Ki67 expression (≥20%) compared with the low SUV/lower RS group (n = 109), but higher PR expression compared with the high SUV/higher RS group (n = 23). Multiple logistic regression analysis showed that high SUV were associated with higher RS (≥26). Conclusions SUV, as a biologic parameter represented using a continuous variable, was found to associate with RS in ER-positive, HER2-negative breast cancer. Further studies may reveal the biology underlying the discordance between the markers.

Ex vivo shear-wave elastography of axillary lymph nodes to predict nodal metastasis in patients with primary breast cancer

Purpose There is still a clinical need to easily evaluate the metastatic status of lymph nodes during breast cancer surgery. We hypothesized that ex vivo shear-wave elastography (SWE) would predict precisely the presence of metastasis in the excised lymph nodes. Methods A total of 63 patients who underwent breast cancer surgery were prospectively enrolled in this study from May 2014 to April 2015. The excised axillary lymph nodes were examined using ex vivo SWE. Metastatic status was confirmed based on the final histopathological diagnosis of the permanent section. Lymph node characteristics and elasticity values measured by ex vivo SWE were assessed for possible association with nodal metastasis. Results A total of 274 lymph nodes, harvested from 63 patients, were examined using ex vivo SWE. The data obtained from 228 of these nodes from 55 patients were included in the analysis. Results showed that 187 lymph nodes (82.0%) were nonmetastatic and 41 lymph nodes (18.0%) were metastatic. There was significant difference between metastatic and nonmetastatic nodes with respect to the mean (45.4 kPa and 17.7 kPa, p<0.001) and maximum (55.3 kPa and 23.2 kPa, p<0.001) stiffness. The elasticity ratio was higher in the metastatic nodes (4.36 and 1.57, p<0.001). Metastatic nodes were significantly larger than nonmetastatic nodes (mean size, 10.5 mm and 7.5 mm, p<0.001). The size of metastatic nodes and nodal stiffness were correlated (correlation coefficient of mean stiffness, r=0.553). The area under curve of mean stiffness, maximum stiffness, and elasticity ratio were 0.794, 0.802, and 0.831, respectively. Conclusion Ex vivo SWE may be a feasible method to predict axillary lymph node metastasis intraoperatively in patients undergoing breast cancer surgery.

Comparison of patients with small (≤2 cm) breast cancer according to adherence to breast screening program

Background We investigated whether adherence to breast screening would yield a clinical benefit even among patients with small breast cancer (≤2 cm) by comparing differences between those who did and did not adhere to breast screening. Methods Patients who were diagnosed with invasive T1 breast cancer and treated at Gangnam Severance Hospital from January 2006 to June 2014 were included. Of the 632 study patients, 450 and 182 were classified as screen-adherent and non-adherent. Adherence to the breast screening program was defined as the completion of breast screening examinations within 3 years before cancer diagnosis. Recurrence-free survival (RFS) and metastasis-free survival (MFS) were compared between the groups. Propensity score matching were applied to compare survival outcome. Results Adherent patients were more likely to have a lower histologic grade (P < 0.001), high estrogen receptor expression (P = 0.040), and lower HER2-positivity (P = 0.026). The adherent group had more favorable subtypes compared to the non-adherent group, with a greater percentage of Luminal/HER2-negative subtype (66.7% vs. 56.5%) and a lower percentage of HER2 subtype (8.3% vs. 16.7%). The RFS and MFS were significantly better in the adherent group (P = 0.003, 0.010, respectively). In the case-matched cohort, superior survival of the adherent group was maintained. Conclusions Adherence to breast screening in patients with small breast tumors was associated with more favorable tumor biology and better prognosis. Our findings suggest that adherence to breast screening might offer clinical benefits in terms of tumor biology as well as early detection.

Chemosensitivity to doxorubicin of ER-positive/HER2-negative breast cancers with high 21-gene recurrence score: A study based on in vitro chemoresponse assay

Aim The 21-gene recurrence score (RS) predicts a clinical benefit of chemotherapy for individuals with ER-positive/HER2-negative breast cancer. Using in vitro chemoresponse assay, we compared the chemosensitivity according to RS in these patients. Method Among the patients with Oncotype Dx assay, we identified 63 patients who had chemotherapy response assays to doxorubicin based on adenosine triphosphate. The degree of chemosensitivity to doxorubicin was translated into the cell death rate (CDR). The RS was also dichotomized with a cutoff of 26. Results Of 63 patients, 34 (54%), 17 (27%), and 12 patients (19%) had a low, intermediate, and high RS, respectively. The mean CDR differed significantly according to categorized RS, with 17.3±10.8 in the low RS group vs. 23.6±16.3 in the intermediate RS group vs. 28.8±12.6 in the high RS group (P = 0.024, One-way ANOVA test). The mean CDR was significantly higher in the higher RS (26≥) group compared with the lower RS (<26) group (P = 0.025, the Student’s t-test), as well as in the high RS (>30) group compared with the low RS (<18) group (P = 0.012, the Student’s t-test). Also, continuous RS and CDR correlated positively (Pearson’s R = 0.337; P = 0.007). High RS demonstrated the odds ratio (OR = 26.33; 95% CI = 1.69–410.0) for predicting tumors with chemosensitivity on the multivariate analysis. Conclusions The chemosensitivity measured by in vitro chemoresponse assay was different according to the RS. Our findings support that tumors with high RS has the chemosensitivity even though they are luminal/HER2-negative tumors.