Neslihan Cabioglu

Increased False Negative Rates in Sentinel Lymph Node Biopsies in Patients with Multi-Focal Breast Cancer

There are few data about the reliability of sentinel node biopsy in patients with multi-focal breast cancer. The aim of this study was to determine the factors affecting the identification and accuracy of the sentinel node, comparing multifocality with other variables, using peritumoral isosulfan blue dye injection technique alone. Between 1998 and 2001, 122 patients with clinically negative nodes from a single institute were eligible for sentinel lymph node biopsies (SLNBs). All patients underwent conventional axillary lymph node dissection (ALND). SLNs were identified in 111 of 122 (91%) cases, and analyzed by hematoxylin and eosin. Twenty-one patients with multi-focal breast cancer were determined by clinical or pathologic examination (gross or microscopic). Success in locating the sentinel node was unrelated to patients age, tumor size, type, location, histological or nuclear grade, multifocality, or a previous surgical biopsy. SLNBs accurately predicted the status of the axilla in 104 of the 111 patients (93.7%), while 18 of the 21 patients with multi-focal breast cancer (85.7%) had successful lymphatic mapping. The false negative (FN) rate was 11.3% among patients with successful SLNBs. Multifocality and tumor size (>2 cm) were associated significantly with decreased accuracy and increased FN rates (for multifocality, p = 0.007 and p = 0.006, and for tumor size >2 cm, p = 0.04 and p = 0.05, respectively) in binary logistic regression analysis, whereas excisional biopsy, tumor location in the upper outer quadrant and patients age did not significantly affect the accuracy and FN rates in univariate analysis. These results suggest sentinel lymph node biopsy using peritumoral isosulfan blue injection method alone can accurately predict axillary status in patients with clinically negative nodes, but patients with multi-focal disease and large tumor size may not be ideal candidates.

Factors predicting the sentinel and non-sentinel lymph node metastases in breast cancer

SummaryThe sentinel lymph node (SLN) is the only focus of axillary metastasis in a significant proportion of patients. In this single institutional study, clinicopathologic characteristics were investigated to determine the factors predicting the status of a SLN biopsy and the metastatic involvement of non-SLNs. Data were retrospectively reveiwed for 400 consecutive patients with clinical T1/T2 N0 breast cancer who underwent a SLN biopsy including axillary and/or internal mammary lymph nodes. The SLNs were evaluated by using the new AJCC staging criteria following multiple sectioning and immunohistochemical (IHC) analyses of nodes. The SLN contained metastases in 148 patients (38.5%) including 18 patients (12.2%) with micrometastases (≤0.2xa0mm) and 130 patients (87.8%) with macrometastases (>0.2xa0cm). Five patients had isolated tumor cells detected by IHC (≤0.2xa0mm, N0i). Patients with tumor size more than 2xa0cm (T1, 29.8% versus T2, 51.6%; OR=2.31, 95% CI, 1.50–3.56) and lymphovascular invasion (LVI-, 30.3% versus LVI+, 51.3%; OR=2.07, 95% CI, 1.34–3.19) were more likely to have positive SLNs in both univariate and multivariate analyses. Among patients with a positive SLN biopsy, those with T2 tumors (versus T1; 63.1% versus 36.9; OR=2.93, 95% CI, 1.43–6.04), macrometastases in SLNs (versus micrometastases; 88.9% versus 11.1%; OR=8.83; 95% CI, 1.82–42.87) and extracapsular node extension (versus without extracapsular node extension; 65.4% versus 34.6%; OR, 2.23; 95% CI, 1.05–4.72) were more likely to have non-SLN metastases in both univariate and multivarite analyses. These results indicate that clinicopathologic factors might be helpful to select patients who were less likely to have negative SLN or non-SLNs. However, additional factors are still needed to be identified to omit surgical axillary staging.

Breast cancer risk factors in Turkish women – a University Hospital based nested case control study

BackgroundBreast cancer has been increased in developing countries, but there are limited data for breast cancer risk factors in these countries. To clarify the risk for breast cancer among the Turkish women, an university hospital based nested case-control study was conducted.MethodsBetween January 2000 and December 2006, a survey was prospectively conducted among women admitted to clinics of Istanbul Medical Faculty for examination and/or treatment by using a questionnaire. Therefore, characteristics of patients diagnosed with breast cancer (n = 1492) were compared with control cases (n = 2167) admitted to hospital for non-neoplastic, non-hormone related diseases.ResultsBreast cancer risk was found to be increased in women with age (≥ 50) [95% confidence interval (CI) 2.42–3.18], induced abortion (95% CI 1.13–1.53), age at first birth (≥ 35) (95% CI 1.62–5.77), body mass index (BMI ≥ 25) (95% CI 1.27–1.68), and a positive family history (95% CI 1.11–1.92). However, decreased breast cancer risk was associated with the duration of education (≥ 13 years) (95% CI 0.62–0.81), presence of spontaneous abortion (95% CI 0.60–0.85), smoking (95% CI 0.61–0.85), breast feeding (95% CI 0.11–0.27), nulliparity (95% CI 0.92–0.98), hormone replacement therapy (HRT) (95% CI 0.26–0.47), and oral contraceptive use (95% CI 0.50–0.69). On multivariable logistic regression analysis, age (≥ 50) years (OR 2.61, 95% CI 2.20–3.11), induced abortion (OR 1.66, 95% CI 1.38–1.99), and oral contraceptive use (OR 0.60, 95% CI 0.48–0.74) were found to be associated with breast cancer risk as statistically significant independent factors.ConclusionThese findings suggest that age and induced abortion were found to be significantly associated with increased breast cancer risk whereas oral contraceptive use was observed to be associated with decreased breast cancer risk among Turkish women in Istanbul.

Increased Lymph Node Positivity in Multifocal and Multicentric Breast Cancer

BACKGROUNDnMultifocal and multicentric (MF/MC) breast cancers have been reported to be associated with increased lymph node metastases. The limited data on this issue prompted us to investigate the pathologic and clinical differences between unifocal and MF/MC breast cancer.nnnSTUDY DESIGNnBetween 1990 and 2002, 1,322 patients with operable invasive breast cancer underwent a definitive operation at our Breast Clinic. Patients with MF/MC breast cancer (n=147, 11%) were compared with patients with unifocal breast cancer (n=1,175; 89%) in terms of pathologic and clinical characteristics.nnnRESULTSnPatients with MF/MC were found to have a higher frequency of lymph node metastases when the largest diameter was used as a tumor size estimate for MF/MC cancer (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 48% and 67%, respectively; p=0.05 and p=0.003, respectively). When the combined diameter assessment was used, the frequency of lymph node positivity was similarly higher in MF/MC patients versus unifocal patients (unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 49% and 61%, respectively; p=0.08 and p=0.046, respectively). At a median followup of 55 months (range 12 to 153 months), 5-year disease-free survival (DFS; unifocal, 88% versus MF/MC, 82%, p=0.14) and overall survival (OS) rates (unifocal, 92% versus MF/MC, 93%, p=0.43) did not show any significant difference between two groups.nnnCONCLUSIONSnOur data suggest that breast tumors with multiple foci have a different biology, with an increased metastatic potential to axillary lymph nodes, regardless of tumor size, that reflects an advanced stage. The clinical relevance of the currently used TNM classification system, which uses the diameter of the largest nodule, is supported by our findings.

Abstract S2-03: Early follow up of a randomized trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer; Turkish study (protocol MF07-01)

Introduction: Previous reports of carefully selected patients presenting with stage IV breast cancer (BC) suggest that surgery on the primary tumor may result in improved survival, but this remains unproven. The MF07-01 trial is a phase III randomized controlled trial of BC women with distant metastases at presentation who receive loco-regional (LR) treatment for intact primary tumor compared with those who do not receive such treatment. Aim: The primary objective of the trial is to compare overall survival (OS) in women treated with or without initial LR resection prior to systemic therapy for de novo stage IV BC. Materials and Methods: At the discretion of the surgeon, LR treatments consisted of either mastectomy or breast conserving surgery with level I-II axillary clearance in clinically or sentinel lymph node positive patients. Radiation therapy to whole breast was required following breast conserving surgery. At the discretion of the medical oncologist standard systemic therapy of either endocrine treatment or chemotherapy (plus trastuzumab for HER2 +) was given to all patients either immediately after randomization (no surgery group) or after surgical resection of the intact primary tumor (surgery group). After consideration of previous retrospective studies, the assumed OS difference between the two groups was determined to be 18% (35% in LR treatment group versus 17% in no-LR treatment group). A 10% drop out rate including lost to follow up was assumed. By using a one sided log-rank test with a 95% confidence (α = 0.05) and a 90% power (β = 0.9), sample size calculation revealed that 271 patients were needed to be randomized. Results: There were 140 women in the surgery group and 138 in the no-surgery group. The mean follow up time was 21.1 ± 14.5 months. The mean age was 51.6 ± 13.2 years and the groups were comparable regarding age, BMI, ER/PR, Her 2, Triple negative, tumor type and size between the groups (all p>0.05). Metastatic patterns included bone only in 45.7%, organ except bone in 28.8%, and bone plus organ in 25.5%. There were a total of 86 (31%) deaths. At 54 months the survival rate was 35% in the surgery group and 31% in the no surgery group (p = 0.24). However, OS was statistically higher in bone only, ER/PR positive and patients younger than 50 years but was lower in the triple negative patients (p Conclusion: In early follow-up of this trial comparing surgery of the primary tumor with no surgery in stage IV BC at presentation OS was similar but there were important subgroup differences; in particular those with solitary bone metastasis have a significant survival benefit and patients with bone metastasis only have a trend toward improved survival with initial surgery. Further follow-up will expand on these important findings. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-03.

Comparison of Intermittent Pneumatic Compression with Manual Lymphatic Drainage for Treatment of Breast Cancer-Related Lymphedema

BACKGROUNDnThe aim of this prospective controlled study was to assess the efficacy of two different combination treatment modalities of lymphedema (LE). Manual lymphatic drainage (MLD) and compression bandage combination (complex decongestive therapy) have been compared with intermittent pneumatic compression (IPC) plus self-lymphatic drainage (SLD).nnnMETHODS AND RESULTSnBoth MLD with compression bandage (complex decongestive therapy) group (Group I, n=15) and IPC with SLD group (Group II, n=15) received treatment for LE 3 days in a week and every other day for 6 weeks. Arm circumferences were measured before and the 1st, 3rd, and 6th weeks of the treatment. EORTC-QLQ and ASES-tests were performed to assess the quality of life before and after 6 week-treatment. Patients in both groups had similar demographic and clinical characteristics. Even though both treatment modalities resulted in significant decrease in the total arm volume (12.2% decrease in Group II and 14.9% decrease in Group I) (p<0.001), no significant difference (p=0.582) was found between those two groups. Similarly, ASES scores were significantly (p=0.001) improved in both Group I and II without any significant difference between the groups. While emotional functioning, fatigue, and pain scores were significantly improved in both groups, global health status, functional and cognitive functioning scores appeared to be improved only in patients of group I.nnnCONCLUSIONSnDifferent treatment modalities consisting of MLD and compression bandage(complex decongestive therapy) or IPC and SLD appear to be effective in the treatment of LE with similar therapeutic efficacy in patients with breast cancer. However, combination modalities including IPC and SLD may be the preferred choices for their applicability at home.

An ultrasensitive tumor enriched flow-cytometric assay for detection of isolated tumor cells in bone marrow of patients with breast cancer

BACKGROUNDnAn ultrasensitive tumor enriched flow-cytometric assay was used to determine its feasibility in detection of isolated tumor cells (ITC) in bone marrow (BM) of patients with breast cancer.nnnMETHODSnEpithelial cells were removed by magnetic microbeads conjugated with an anti-cytokeratin 7/8 monoclonal antibody to enrich tumor cells in BM samples. A specific gate for MCF-7 breast cancer cells (gate(MCF-7 cells)) was also taken into consideration in addition to a gate including all enriched BM cells (gate(enriched BM cells)) in flow-cytometric analysis to enhance the specificity of the method.nnnRESULTSnNineteen patients with stage I/II were evaluated. Ten patients (53%) were found to have cytokeratin positive (CK(+)) cells according to the gate(enriched BM cells) whereas 6 patients (32%) had CK(+) cells when the gate(MCF-7 cells) was taken into account.nnnCONCLUSIONSnNew strategies in nonmorphological ultrasensitive techniques might be useful to categorize patients with ITCs having different tumor morphology and characteristics.

Factors predicting microinvasion in Ductal Carcinoma in situ.

BACKGROUNDnWhether sentinel lymph node biopsy (SLNB) should be performed in patients with pure ductal carcinoma in situ (DCIS) of the breast has been a question of debate over the last decade. The aim of this study was to identify factors associated with microinvasive disease and determine the criteria for performing SLNB in patients with DCIS.nnnMATERIALS AND METHODSn125 patients with DCIS who underwent surgery between January 2000 and December 2008 were reviewed to identify factors associated with DCIS and DCIS with microinvasion (DCISM).nnnRESULTSn88 patients (70.4%) had pure DCIS and 37 (29.6%) had DCISM. Among 33 DCIS patients who underwent SLNB, one patient (3.3%) was found to have isolated tumor cells in her biopsy, whereas 1 of 14 (37.8%) patients with DCISM had micrometastasis (7.1%). Similarly, of 16 patients (18.2%) with pure DCIS and axillary lymph node dissection (ALND) without SLNB, none had lymph node metastasis. Furthermore, of 20 patients with DCISM and ALND, only one (5%) had metastasis. In multivariate analysis, the presence of comedo necrosis [relative risk (RR)=4.1, 95% confidence interval (CI)=1.6-10.6, P=0.004], and hormone receptor (ER or PR) negativity (RR=4.0, 95%CI=1.5-11, P=0.007), were found to be significantly associated with microinvasion.nnnCONCLUSIONSnOur findings suggest patients presenting with a preoperative diagnosis of DCIS associated with comedo necrosis or hormone receptor negativity are more likely to have a microinvasive component in definitive pathology following surgery, and should be considered for SLNB procedure along with patients who will undergo mastectomy due to DCIS.

Survey on a mammographic screening program in Istanbul, Turkey.

Abstract:u2002 Breast cancers in Turkey tend to be diagnosed at advanced stages due to lack of organized comprehensive mammographic screening. In this study, factors associated with having a mammogram among healthy women of screening age in Bahcesehir county, a region in Istanbul, were investigated to assess the feasibility of organized breast cancer screening in Turkey. In this cross‐sectional study, 659 healthy women aged between 40 and 69u2003years were surveyed. A multiple‐choice questionnaire was used to obtain information regarding patient demographics, family history of cancer, and patient knowledge on mammographic screening. Factors associated with increased likelihood of having a mammogram included age older than 50 (ORu2003=u20031.75; 95% CIu2003=u20031.23–2.49), higher educational level (high school or university graduate; ORu2003=u20031.55; 95% CIu2003=u20031.07–2.25), and undergoing periodic gynecologic examinations (ORu2003=u20035.53; 95% CIu2003= 3.88–7.89). Women aged between 40 and 49 years, who were most likely to have a mammogram within the last 2u2003years were characterized by a higher educational level (ORu2003=u20031.94; 95% CIu2003=u20031.14–3.31), periodic gynecologic examinations (ORu2003=u20034.06; 95% CIu2003=u20032.53–6.51), and a first or second degree family history of breast cancer (ORu2003=u20032.2; 95% CIu2003= 1.06–4.50). In contrast, women aged between 50 and 69u2003years were more likely to have undergone mammography within the previous 2u2003years if they also had undergone periodic gynecologic examinations (ORu2003=u20038.63; 5.04–14.77). Our findings suggest that women of lower educational level and those who do not undergo routine wellness visits with their gynecologist will need to be specifically targeted for educational outreach to achieve broad screening compliance within the population.

Biological considerations in locally advanced breast cancer treated with anthracycline-based neoadjuvant chemotherapy : thymidine labelling index is an independent indicator of clinical outcome

The present retrospective study aims to determine the clinical value of thymidine labelling index (TLI) together with other established clinical and biological factors in 116 locally advanced breast cancer (LABC) patients treated with anthracycline-based neoadjuvant chemotherapy, surgery, adjuvant chemotherapy and radiotherapy. TLI was determined in 71 LABC patients with a median of 2.62% (0–23.64%) and a mean of 4.71%±5.54. As a result of neoadjuvant chemotherapy, 85 patients (73%) responded to chemotherapy (CT), whereas 31 patients were unresponsive (27%). No relationship has been found between the pretreatment biological variables including TLI, estrogen receptor (ER), progesteron receptor (PgR) status and clinical parameters such as the chemotherapy response rates and axillary lymph node involvement following chemotherapy. Median follow-up was 35 months (18–97 months) and the 3-year overall survival (OS) and disease free survival (DFS) rates were 71.6% and 52.2%, respectively. In univariate analysis, patients with inflammatory breast cancer, high TLI-index (≥2.62%), lymph node (LN) positivity or >3 positive lymph nodes following neoadjuvant chemotherapy and without any response to neoadjuvant chemotherapy were found to have worse DFS and OS-rates and high local and systemic recurrence rates. In multivariate analysis, TLI was estimated as the most powerful independent factor affecting the OS in LABC patients among the other established clinical and biological parameters (p=0.02). These results suggest that TLI is an important independent indicator of clinical outcome in patients with LABC and these patients with high TLI levels require more effective treatment modalities.