Jonghan Yu

Effect of multiple invasive foci on breast cancer outcomes according to the molecular subtypes: a report from the Korean Breast Cancer Society

BACKGROUND In this study, the prognostic impact of the presence of the multifocal or multicentric tumor (MMT) and its association with molecular subtypes were investigated. PATIENTS AND METHODS We investigated the breast cancer metastasis and survival in patients with multifocal or multicentric invasive foci in the same breast. The study population includes 2882 patients in the Seoul National University Hospital Breast Care Center (SNUHBCC) dataset and 41 179 patients in Korean Breast Cancer Registry (KBCR) dataset. RESULTS From SNUHBCC dataset, we observed a significant role of MMT in developing distant metastasis and death when the tumors were triple-negative subtype. This subtype-specific prognostic importance of MMT in overall survival was also seen in KBCR dataset (HR, 1.32; 95% CI, 1.02-1.69). In tumors <2 cm, the hazard ratios (HRs) for node metastasis and death were similar along the tumor size change in triple-negative subtype, while other subtypes showed a stepwise increment, suggesting the biologic importance of small invasive foci in this subtype. CONCLUSIONS Our results demonstrate the prognostic importance of MMT in patients with triple-negative breast cancers. Small additional invasive foci in triple-negative breast cancer patients should be considered as clinically relevant tumor deposits.

Adjuvant endocrine therapy alone in patients with node-positive, luminal A type breast cancer

Abstract Luminal A breast cancer has a much better prognosis than other subtypes, with a low risk of local or regional recurrence. However, there is controversy around under- versus overtreatment with regard to adjuvant treatment of node-positive, luminal A breast cancer. The purpose of this study was to identify whether adjuvant systemic chemotherapy has any benefit in node-positive, luminal A breast cancer and to evaluate feasibility of endocrine therapy without chemotherapy in this group. This was a retrospective study of 11,025 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between January 2004 and December 2013. Luminal A subtype was defined as ER+, HER2-, and Ki-67 < 14%. We compared AC based (AC: doxorubicin or epirubicin, plus cyclophosphamide) adjuvant chemotherapy versus endocrine therapy without chemotherapy in patients with node-positive, luminal A breast cancer. We performed 1: n matching, with a maximum n of 8 on endocrine therapy group (n = 50) to chemotherapy group (n = 642). The median age of the patients in each group at the time of surgery was 58.3 ± 9.5 years in the chemotherapy group and 58.7 ± 11.7 in the endocrine therapy only group. The median follow-up time was 51.9 months (range, 1–125 months). In multivariable analysis, omission of adjuvant chemotherapy in luminal A cancer had no influence on OS and DFS. Axillary lymph node metastasis and progesterone receptor (PR) status were significantly different between the endocrine therapy alone group and the chemotherapy group in terms of OS. Nuclear grade, PR status, and adjuvant radiotherapy were significantly different between the endocrine therapy alone group and the chemotherapy group with regard to DFS. In survival analysis, there were no differences in OS (P = .137) and DFS (P = .225) between the 2 groups. Adjuvant chemotherapy could provide little benefit to postmenopausal patients with luminal A, node-positive breast cancer, and endocrine therapy alone may help reduce morbidity. Future studies with a large number of patients and longer follow-up time are necessary to determine whether chemotherapy might be avoided in this patient population.

Association of Human Epidermal Growth Factor Receptor 2 with Radiotherapy Resistance in Patients with T1N0M0 Breast Cancer

Purpose Preclinical studies have shown that human epidermal growth factor receptor 2 (HER2) status is associated with resistance to radiotherapy (RT). In this study, we evaluated the overall survival of a T1N0M0 breast cancer cohort in Korea according to the use of RT and the HER2 status. Methods We analyzed data collected from 11,552 patients with invasive breast cancer who were enrolled in the Korean Breast Cancer Society Registration Program between 1999 and 2007. Data on the TNM stage, estrogen receptor status, progesterone receptor status, HER2 status, operation method, and the use of RT were analyzed. Results The median follow-up period was 51 months. A significant improvement in overall survival after RT was observed only in the HER2(-) group. In this group, the 10-year overall survival rate was 95.5% for patients who did not receive RT and 96.3% for patients who received RT (p=0.037). In contrast, in the HER2(+) group, RT was not associated with a survival benefit (p=0.887). Multivariate analysis showed that RT was significantly associated with a reduction in mortality in the HER2(-) group (hazard ratio, 0.738; 95% confidence interval, 0.549-0.993; p=0.045). Conclusion We found that postoperative RT was not associated with a survival benefit in HER2(+) breast cancer patients, suggesting that HER2(+) breast cancers could be RT resistant.

Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells

Background/Aims: Transforming growth factor-beta proteins (TGF-βs) are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-β1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-β1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-β1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-β1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-β receptor I inhibitor, SB431542. In addition, TGF-β1–induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-β1, but not TGF-β2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-β1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC.

Fertility Rates in Young Korean Breast Cancer Patients Treated with Gonadotropin-Releasing Hormone and Chemotherapy

Purpose Gonadotropin-releasing hormone (GnRH) agonists have been used with adjuvant chemotherapy to protect ovarian function. However, there are no data on the actual pregnancy rates among young breast cancer patients receiving GnRH agonists and concurrent chemotherapy in Korea. Methods Among patients who underwent surgery from January 2002 to April 2012, premenopausal patients aged between 20 and 40 years were included in the analysis. We retrospectively reviewed clinicopathologic features (e.g., age, obstetric and menstruation history), recurrence, and survival status. The rate of resumption of menstruation was calculated in all patients. In the married group, pregnancy and delivery rates were also recorded. Results Among 101 patients, 19 were lost to follow-up and 82 were eligible for the analysis. Among them, 31 were married, 10 of 51 got married, and 41 remained unmarried through the follow-up period. Among the married patients, 15 became pregnant and gave birth to 19 babies, whereas 26 did not become pregnant. The pregnancy rate in the married group was 50.0% (15/30). Three of 15 pregnancies (20.0%) were multiparous. Most of the delivered babies were healthy and 80.0% of patients had no problems breastfeeding (12/15). More than half the patients in all groups recovered menstrual status within 12 months. Conclusion Fifty percent of young breast cancer patients who attempted pregnancy succeeded in pregnancy after adjuvant chemotherapy and GnRH agonists. Further studies that include control groups are required to confirm whether the use of GnRH agonists improves pregnancy.

Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer

Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3-month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co-variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen (P < 0.001), NDM (P < 0.001), endoxifen/NDM (P < 0.001), NDM/tamoxifen (P < 0.001), and 4-OH tamoxifen/tamoxifen (P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status.

A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients

PurposeThe value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established.MethodsPre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed.ResultsHigh pre-NAC TILs, clinical nodal stage 0–1 (cN0–1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses.ConclusionsHigh pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Conditional disease-free survival among patients with breast cancer.

Abstract Conditional disease-free survival (CDFS) reflects changes over time. Because traditional disease-free survival (DFS) is estimated from the date of diagnosis, it is limited in the ability to predict risk of recurrence in patients who have been disease free. In this study, we determined CDFS of breast cancer patients and estimated the prognostic factors for DFS. We retrospectively reviewed clinical data of 7587 consecutive patients who underwent curative surgery for breast cancer between January 2004 and December 2013 at Samsung Medical Center. Univariate and multivariate analyses were performed to identify risk factors for DFS, which was computed using the Kaplan–Meier method. CDFS rates were based on cumulative DFS estimates. Median follow-up duration was 20.59 months. Three-year DFS was 93.46% at baseline. Three-year CDFS survival estimates for patients who had been disease free for 1, 2, 3, 4, and 5 years after treatment were calculated as 92.84%, 92.37%, 93.03%, 89.41%, and 79.64%, respectively. Three-year CDFS increased continuously each year after 1 year of DFS in hormone receptor (HR)-negative patients but decreased each year in HR-positive patients. In HR-positive patients who are disease free after 3 years, continuous care including surveillance and metastases workup should be considered, although this is not recommended in the current guidelines. On the other hand, the social costs may be reduced in HR-negative patients by extending the surveillance interval. Further studies are needed to identify indicators of DFS prognosis in breast cancer patients.