Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer.

BACKGROUND: There are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (CYP2D6) polymor-phisms. AIM: To evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes. METHODS: Eighty-two women were recruited. Seventy-eight completed CYP2D6 genotyping and were categorized into poor, intermediate (IM) and extensive or ultra metabolizer phenotypes. Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent. RESULTS: More than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [P = 0.743, hazard ratio (HR): 1.441, 95% confidence interval (CI): 0.191 to 10.17 and P = 0.798, HR: 1.327, 95%CI: 0.172 to 9.915, respectively]. Women receiving aromatase inhibitors also appeared to have a better, but also nonsignificant, 5-year recurrence-free and overall survival (P = 0.253, HR: 0.368, 95%CI: 0.031 to 0.258 and P = 0.292, HR: 0.252, 95%CI: 0.005 to 4.951, respectively). CONCLUSION: The IM phenotype was highly prevalent but was not associated with clinical outcome.

Germline breast cancer susceptibility genes, tumor characteristics, and survival.

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]). CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

Mastectomy rates remain high in Singapore and are not associated with poorer survival after adjusting for age.

Recent reports have suggested that women undergoing mastectomy, instead of wide local excision (WLE) for Stage I and II breast cancers have poorer overall survival. This is particularly important in our setting where mastectomy rates are high. In this study, we evaluated the trends in mastectomy and WLE over a 10-year period at a single institute, identified factors more common among women who underwent mastectomy and specifically examined the effect of surgery on outcome. Retrospective review was performed of 2244 women who underwent curative surgery for non-metastatic breast cancer at our institute from 1st January 2001 to 31st December 2010. Mastectomy rates remained high over the 10 years, ranging from 43 to 59 %. Older women, those with symptoms, larger tumours and clinical nodal involvement were more likely to receive mastectomy (P < 0.05). The type of surgery (mastectomy or WLE) did not affect survival in women with ductal carcinoma-in situ, while women with invasive cancer appeared to survive longer when treated with WLE (P < 0.01). Surgery type was not an independent predictor of overall survival and the survival advantage with WLE did not remain after adjusting for age, implying that the effect on survival had been confounded by the fact that older women tended to undergo mastectomy. Mastectomy remains common among our local women, with further studies being needed to evaluate factors involved in decision-making. Older women and those with significant co-morbidities were more likely to undergo mastectomy and this contributed to an apparent survival advantage following WLE.

Extent of margin involvement, lymphovascular invasion, and extensive intraductal component predict for residual disease after wide local excision for breast cancer.

UNLABELLED: In the present study, we identified predictors of residual disease after an inadequate wide local excision. Residual tumor was more likely when tumor was present at the inked margin, when more than a single radial margin was affected, and in tumors associated with lymphovascular invasion and an extensive intraductal component. BACKGROUND: Positive margins after wide local excision (WLE) increase the probability of residual disease, and additional surgery is often recommended. However, residual tumor will be found in only two thirds of cases, suggesting that additional surgery can be avoided in many instances. In the present study, we sought to establish the frequency of residual tumor when the surgical margins are inadequate and to identify factors that predict for residual tumor. MATERIALS AND METHODS: A retrospective review was performed of 720 consecutive patients who had undergone WLE for ductal carcinoma in situ and nonmetastatic breast cancer at a single unit from January 1, 2004 to December 31, 2010. RESULTS: At least a single radial margin was affected (either involved or close, defined as tumor < 1 mm from the margin) in 244 patients who had undergone WLE, and either the anterior or posterior margin was affected in another 103 patients. Reoperation was performed in 215 patients with affected radial margins and 9 others with affected anterior or posterior margins. Residual disease was found in 98 of 224 patients (43.8%) and was more likely when tumor was present at the inked margin, when > 1 radial margin was affected, and when lymphovascular invasion (LVI) or an extensive intraductal component (EIC) was present. The association with tumor size was of borderline significance. No association was found with tumor histologic type or patient age. CONCLUSION: Additional evaluation is needed to determine whether additional surgery can be safely omitted in women with tumors without LVI or EIC when a single radial margin has been deemed to be close.

Limiting the use of primary endocrine therapy in elderly women with breast cancer.

Primary endocrine therapy (PET) is often included as a treatment option in elderly women with operable breast cancer. Elderly women tend to have pre-existing comorbidities and are often reluctant to undergo surgery. The benefit of surgery needs to be weighed against a relatively higher potential for operative morbidity and mortality, and a limited life expectancy. But while PET can provide relatively good locoregional control, it is not curative in nature and the possibility of local complications and metastasis remains. We retrospectively reviewed the outcome of PET in a series of 19 elderly women, older than 70 years of age, who had presented with operable non-metastatic breast cancer. Only about a third of these women were deemed medically unfit for surgery; the rest had declined surgery. Compliance was an issue, with almost half of these patients defaulting treatment and follow-up. Local control was achieved in most patients, but disease progression did occur in 5 patients. Three of these patients received additional treatment; which included surgery in 1 patient. PET should therefore not be considered an equivalent alternative to surgery in elderly women who were fi t to undergo surgery. However, having observed that only 1 of the 6 deaths in our study was related to breast cancer, PET does have a role in women whose life expectancy is more likely to be limited by coexisting morbidities than the breast cancer itself.

The use of traditional Chinese medicine among breast cancer patients: implications for the clinician.

INTRODUCTION: Traditional Chinese Medicine or Traditional Complementary Medicine (TCM) is commonly used in our culture. There are several concerns regarding its use in patients undergoing conventional treatments for breast cancer. In this study, we aimed to evaluate the prevalence and pattern of TCM use among our breast cancer patients, and to identify patients who were most likely to choose TCM. MATERIALS AND METHODS: A total of 300 patients on active follow-up with Breast Service at Tan Tock Seng Hospital were interviewed using a structured questionnaire. RESULTS: A total of 35% (104 of 296) of patients reported using TCM. The majority of the patients were introduced to TCM by family and friends following the diagnosis of breast cancer. All except 3 patients continued with recommended conventional therapy although most did not inform their clinicians of TCM use. None of the patients reported any serious adverse events and 75% of them perceived a benefit from TCM use. Younger patients and those of Chinese ethnicity were more likely to use TCM (P <0.01 and P = 0.03 respectively). There was no significant difference in the dialect group, religious beliefs and educational level between the 2 groups (P >0.05). CONCLUSION: TCM use is common among our breast cancer patients, particularly the younger women. However, most patients do not inform their clinicians of TCM use while on recommended conventional therapies. It is therefore important for clinicians to initiate discussions regarding TCM use in order to be aware of potential unwanted drug interactions.

Sentinel Lymph Node Biopsy Should Be Included with the Initial Surgery for High-Risk Ductal Carcinoma-In-Situ.

Background. A proportion of those diagnosed preoperatively with ductal carcinoma-in-situ (DCIS) will be histologically upgraded to invasive carcinoma. Repeat surgery for sentinel lymph node (SLN) biopsy will be required if it had not been included with the initial surgery. We reviewed the outcome of SLN biopsy performed with the initial surgery based on a preoperative diagnosis of DCIS and aimed to identify patients at risk of histological upgrade. Methods. Retrospective review of 294 consecutive female patients diagnosed with DCIS was performed at our institute from January 1, 2001, to December 31, 2008. Results. Of the 294 patients, 132 (44.9%) underwent SLN biopsy together with the initial surgery. The SLN was positive for metastases in 5 patients, all of whom had tumours that were histologically upgraded. Histological upgrade also occurred in 43 of the 127 patients (33.9%) in whom the SLN was negative for metastases. On multivariate analysis, histological upgrade was more likely if a mass was detected on mammogram, if the preoperative diagnosis was obtained with core biopsy and if microinvasion was reported in the biopsy. Conclusion. Patients in whom a preoperative diagnosis of DCIS is likely to be upgraded to invasive carcinoma will benefit from SLN biopsy being performed with the initial surgery.

Achieving breast cancer surgery in a single setting with intraoperative frozen section analysis of the sentinel lymph node.

BACKGROUND: Current guidelines recommend full axillary lymph node dissection (ALND) whenever the SLN is positive for metastases. In our institute, we aim to complete surgery in a single setting and base the decision for ALND on the intraoperative FS analysis of the SLN. In this study, we evaluate the efficacy this practice in terms of the accuracy of FS analysis, patient recall rate, and additional time required for FS analysis. MATERIALS AND METHODS: Retrospective review was performed of 586 patients who underwent SLN biopsy at our institution from January 1, 2006 to December 31, 2010. Intraoperative FS analysis was routinely performed in all cases with a preoperative diagnosis of invasive breast cancer and in selected cases of ductal carcinoma in situ according to surgeon preference. RESULTS: The SLN was positive for metastases in 123 (22.7%) patients; this was identified on FS analysis in 107 patients. FS analysis had a sensitivity of 87.0% and specificity of 100% and resulted in a patient recall rate of 3%. Micrometastasis accounted for most of the false negative FS results. These deposits were mostly detected only on deeper sectioning of the permanent sections of the SLN. An invasive lobular histology and lymphovascular invasion were found to be independent predictors of a false negative FS on multivariate analysis (P < .01). Intraoperative FS did not significantly prolong operating times. CONCLUSION: Intraoperative FS analysis is an accurate and efficient means of rapid SLN assessment and allows ALND to be completed in a single setting.

Surgical excision of intraductal breast papilloma diagnosed on core biopsy.

BACKGROUND: The need for surgical excision of benign papillary lesions diagnosed on core biopsy remains debatable. This lack of consensus arises because although there is a possibility of histological underestimation, there are as yet no reliable predictors of malignancy. We therefore aimed to evaluate the incidence of histological underestimation in our practice, and to identify factors that predict for this, in order to reduce unnecessary surgery without missing out on possible malignancy. METHODS: Retrospective review of 106 patients diagnosed with a papillary lesion on percutaneous image-guided core biopsy was performed between 1 January 2005 and 31 December 2008. The presence of atypia on core biopsy and the presence of malignancy in the surgical specimen were correlated with standard clinical, radiological and pathological features. RESULTS: Histological underestimation occurred in 15 of 81 patients (19%). Malignancy was more likely when atypia was present in the core biopsy (P= 0.04, OR 5.17). Otherwise, a final diagnosis of malignancy was not correlated with any clinical or radiological features (P > 0.05). The presence of atypia was also not correlated with any clinical or radiological features. CONCLUSION: In our study, 19% of patients with a benign papillary lesion diagnosed on core biopsy were found to have atypical ductal hyperplasia or malignancy following surgery. In view of this, together with the absence of reliable predictive factors for malignancy, we recommend surgical excision of all papillary lesions diagnosed on core biopsy.

Predictors of nonsentinel nodal involvement to aid intraoperative decision making in breast cancer patients with positive sentinel lymph nodes.

Background. Up to 60% of patients with a positive sentinel lymph node (SLN) have no additional nodal involvement and do not benefit from completion axillary lymph node dissection (ALND). We aim to identify factors predicting for non-SLN involvement and to validate the MSKCC nomogram and Tenon score in our population. Methods. Retrospective review was performed of 110 consecutive patients with positive SLNs who underwent ALND over an 8-year period. Results. Fifty patients (45%) had non-SLN involvement. Non-SLN involvement correlated positively with the number of positive SLNs (P = 0.04), macrometastasis (P = 0.01), and inversely with the total number of SLNs harvested (P = 0.03). The MSKCC nomogram and Tenon score both failed to perform as previously reported. Conclusions. The MSKCC nomogram and Tenon score have limited value in our practice. Instead, we identified three independent predictors, which are more relevant in guiding the intraoperative decision for ALND.