Isabel T. Rubio

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

BACKGROUND The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Subareolar Versus Peritumoral Injection for Location of the Sentinel Lymph Node

BACKGROUND Sentinel lymph node (SLN) biopsy is fast becoming the standard for testing lymph node involvement in many institutions. However, questions remain as to the best method of injection. The authors hypothesized that a subareolar injection of material would drain to the same lymph node as a peritumoral injection, regardless of the location of the tumor. METHODS To test this theory, 68 patients with 69 operable invasive breast carcinomas and clinically node-negative disease were enrolled in this single-institution Institutional Review Board-approved trial. Patients were injected with 1.0 mCi of technetium-99 sulfur colloid (unfiltered) in the subareolar area of the tumor-bearing breast. Each patient received an injection of 2 to 5 cc of isosulfan blue around the tumor. Radioactive SLNs were identified using a hand-held gamma detector probe. RESULTS The average age of patients entered into this trial was 55.2 +/- 13.4 years. The average size of the tumors was 1.48 +/- 1.0 cm. Thirty-two percent of the patients had undergone previous excisional breast biopsies. Of the 69 lesions, 62 (89.9%) had SLNs located with the blue dye and 65 (94.2%) with the technetium. In four patients, the SLN was not located with either method. All blue SLNs were also radioactive. All located SLNs were in the axilla. Of the 62 patients in which the SLNs were located with both methods, an average of 1.5 +/- 0.7 SLNs were found per patient, of which 23.2% had metastatic disease. All four patients in which no SLN was located with either method had undergone prior excisional biopsies. CONCLUSIONS The results of this study suggest that subareolar injection of technetium is as accurate as peritumoral injection of blue dye. Central injection is easy and avoids the necessity for image-guided injection of nonpalpable breast lesions. Finally, subareolar injection of technetium avoids the problem of overlap of the radioactive zone of diffusion of the injection site with the radioactive sentinel lymph node, particularly in medial and upper outer quadrant lesions.

PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

UNLABELLED PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.

Use of touch preps for intraoperative diagnosis of sentinel lymph node metastases in breast cancer

AbstractBackground: Intraoperative touch prep (TP) is highly accurate for determining positive breast cancer margins and thereby reducing the need for second surgeries. It also may be useful in determining the status of the sentinel lymph node (SLN) during the initial surgical resection. The objective of this study was to test the ability of intraoperative TP to predict metastatic disease and, thus, the necessity for axillary lymph node dissection (ALND) at the time of SLN biopsy. Methods: Fifty-five patients with invasive breast cancer were entered in the SLN biopsy protocol. The SLN was identified by gamma probe, dissected, and sent to pathology for TP and permanent sections. Level I and II ALND was then performed. Any radiolabeled LN in the lymphadenectomy specimen also was sent for TP and permanent sections. Results: A total of 124 radiolabeled lymph nodes (LNs) were submitted for TP; of these, 93 (75%) were SLNs. Pathologic diagnosis by TP was correct compared with permanent sections for 99.2% of the nodes. There were no false positives. There was one (0.8%) false negative. The positive predictive value was 100% and the negative predictive value was 99%. Sensitivity was 95.7% and specificity was 100%. Conclusions: TP is a simple, quick, and accurate method for detecting metastatic disease in the SLN and, when used intraoperatively, enables the surgeon to determine whether or not an ALND is necessary at the time of the initial surgery.

BRCA in breast cancer: ESMO Clinical Practice Guidelines

BRCA in breast cancer: ESMO Clinical Practice Guidelines J. Balmana, O. Diez, I. Rubio & M. Castiglione On behalf of the ESMO Guidelines Working Group* Department of Medical Oncology; Oncogenetics Laboratory, University Hospital Vall d’Hebron; Vall d’Hebron Institute of Oncology (VHIO); Breast Cancer Surgical Unit, Breast Cancer Center, University Hospital Vall d’Hebron, Barcelona, Spain; RGT, University of Geneva, Geneva, Switzerland

The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase.

BACKGROUND The MINDACT (Microarray In Node-negative and 1-3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. METHODS MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered. RESULTS During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7-11.8%; P<.0001). Compliance with the treatment decision was high (>92%). CONCLUSIONS The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.

Sentinel lymph node biopsy for staging breast cancer

BACKGROUND Determination of axillary nodal status is essential for the staging of breast cancer since nodal status is one of the most important predictors of survival. The objective of this study was to test the hypothesis that the histology of the first draining lymph node (LN) accurately predicts the histology of the rest of the axillary LNs. METHODS Fifty-five patients with operable invasive breast carcinoma and clinically negative axillary lymph nodes were studied. Patients were injected with Technetium-99 (99Tc) sulfur colloid around the primary tumor. A hand-held gamma detector probe was used to identify the sentinel LN (SLN). After the SLN was identified and removed, a level I and II lymphadenectomy was performed. RESULTS The SLN was identified in 53 (96.3%) of the 55 patients entered into the trial. The sensitivity was 88.2% and the specificity was 100%. The positive predictive value was 100% and the negative predictive value was 94.6%. The accuracy of the study was 96.2%. CONCLUSIONS The SLN biopsy for breast cancer staging is highly accurate in our hands and has the potential to decrease the morbidity and cost of managing patients with breast cancer without compromise of staging.

Intraoperative ultrasound-guided breast biopsy

BACKGROUND Biopsy of nonpalpable lesions has increased during the last decade. Commonly these lesions are excised using preoperative wire localization. We describe a technique of intraoperative ultrasound-guided breast biopsy that allows easier excision and aids in obtaining surgical margins in breast cancer. METHODS Intraoperative ultrasound was performed on 81 lesions. Ultrasound was used in an attempt to approximate a 1 cm margin on malignant lesions. RESULTS All attempts to localize lesions with ultrasound in surgery were successful (81 of 81). Ultrasound-guided surgery was accurate in predicting margins in 24 of 25 malignant lesions. No complications resulted. CONCLUSION Ultrasound proved to be an effective technique for localizing and excising breast lesions. Benefits may include improving patient comfort, avoiding complications of needle localization breast biopsy, and simplifying the scheduling of surgical procedures. Additionally, this procedure may be used to obtain adequate surgical margins and thus reduce the recurrence rate of breast cancer.

Intraoperative touch preparation for sentinel lymph node biopsy: A 4-year experience

BackgroundThe optimal technique for intraoperative pathologic examination of sentinel lymph nodes (SLNs) is still controversial. Recent small series report sensitivity between 60% and 100% for various techniques. The aim of this study was to evaluate our long-term experience with touch preparation cytology (TPC) and frozen section (FS) in the intraoperative examination of SLNs for breast cancer.MethodsA total of 247 patients with operable breast cancer underwent an SLN biopsy for staging of the axilla. The SLN was identified by99mTc-labeled sulfur colloid unfiltered dye, blue dye, or both and dissected, and then intraoperative TPC or FS and permanent section, or both, were performed.ResultsA total of 479 SLNs were submitted for TPC and permanent hematoxylin and eosin. A total of 68 SLNs were positive by hematoxylin and eosin; 65 SLNs were positive by TPC, with a false-negative rate of 5.8%. The sensitivity for TPC was 94.2%, with a false-positive rate of 0.2%. A total of 165 SLNs were submitted for FS, with a sensitivity of 85.7% and a specificity of 98.6%. The false-positive rate was 1.4%, with a false-negative rate of 15.8%.ConclusionsIn a large series, TPC is as accurate as FS but is simpler and faster in the detection of intraoperative metastasis in SLNs for breast cancer.

Prediction of non-sentinel lymph node metastasis in early breast cancer by assessing total tumoral load in the sentinel lymph node by molecular assay

INTRODUCTION The one-step nucleic acid amplification (OSNA) is a molecular procedure that yields a semiquantitative result for detection of nodal metastasis. Size of metastasis in the sentinel lymph node (SLN) by conventional histology has been described as a predictive factor for additional axillary metastasis. The objective of this study is to quantify intraoperatively the total tumoral load (TTL) in the positive SLNs assessed by OSNA and to determine whether this TTL predicts non-SLN metastasis in patients with clinically node negative early stage breast cancer. METHODS 306 patients with cT1-3N0 invasive breast cancer who had undergone intraoperative SLN evaluation by OSNA were included. TTL was defined as the addition of CK19 mRNA copies of each positive SLN (copies/μL). RESULTS TTL was a predictive factor of additional non-SLN metastasis in the complete axillary lymph node dissection (cALND) (OR, 1.67; 95% CI, 1.18-2.35). In the multivariate analysis, the TTL was a predictor of non-SLN metastasis in HR positive patients (OR, 1.69; 95% CI, 1.19-2.41). In our cohort of patients, with a TTL ≤1.2 × 10(5) copies/μL, there was a specificity of 85.3% and negative predictive value (NPV) of 80%. If we consider only the HR positive patients, with a TTL ≤5 × 10(5) copies/μL there was a specificity of 86.7% and NPV of 83.7%. CONCLUSIONS TTL assessed by OSNA assay predicts for additional non-SLN metastasis and this intraoperative tool can help guiding decisions on performing a cALND in breast cancer patients.