Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.

PURPOSE: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort. METHODS: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs. RESULTS: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC. CONCLUSION: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.

Reducing chronic breast cancer-related lymphedema utilizing a program of prospective surveillance with bioimpedance spectroscopy.

This single-institution experience evaluated the use of bioimpedance spectroscopy to facilitate early detection and treatment of breast cancer-related lymphedema (BCRL) in a cohort of 596 patients (79.6% high risk). Seventy-three patients (12%) developed an elevated L-Dex score with axillary lymph node dissection (P < .001), taxane chemotherapy (P = .008), and regional nodal irradiation (P < .001) associated. At last follow-up, only 18 patients (3%) had unresolved clinically significant BCRL requiring complete decongestive physiotherapy. This rate of BCRL is lower than reported in contemporary studies, supporting recent NCCN guidelines promoting prospective screening, education and intervention for BCRL.

Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial.

Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00003855.

Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial.

BACKGROUND AND OBJECTIVE: The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results. METHODS: ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups. RESULTS: Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P < 0.001). ALND, as expected, also removed more positive lymph nodes (P < 0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36). CONCLUSION: Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Can breast surgeons provide breast cancer genetic testing? An American Society of Breast Surgeons survey.

BACKGROUND: Whether breast cancer surgeons are adequately trained, skilled, and experienced to provide breast cancer genetic assessment, testing, and counseling came under debate in September 2013 when a major third-party payer excluded nongenetics specialists from ordering such testing. A literature search having failed to uncover any study on breast surgeons' skill and practice in this area, the American Society of Breast Surgeons (ASBrS) surveyed its members on their experience with the recognized crucial components of such testing. METHODS: In late 2013, ASBrS e-mailed a link to an online questionnaire to its U.S. members (n = 2,603) requesting a self-assessment of skills and experience in genetic assessment, testing, interpretation, and counseling. After approximately 6 weeks, the results were collated and evaluated. RESULTS: By January 2, 2014, 907 responses (34.84 %) had arrived from breast surgeons nationwide working in academic settings (20 %), solo or small group private practice (39 %), large multispecialty groups (18 %), and other settings. More than half said they performed 3-generation pedigrees, ordered genetic testing, and provided pre- and posttest counseling. Most noted that they would welcome continuing educational support in genetics. CONCLUSIONS: Currently the majority of breast surgeons provide genetic counseling and testing services to their patients. They report practices that meet or exceed recognized guidelines, including the necessary elements and processes for best practices in breast cancer genetics test counseling. Because breast cancer genetic testing is grossly underutilized relative to the size of the U.S. BRCA mutation carrier population, these appropriate services should not be restricted but rather supported and expanded.

PET/CT in the management of thyroid cancers.

OBJECTIVE: Thyroid cancer is the most common endocrine cancer. This review evaluates the established use of (18)F-FDG PET/CT in papillary, follicular, Hürthle cell, anaplastic, and medullary thyroid cancers. The significance of incidental diffuse and focal thyroid FDG uptake is discussed. The evolving value of non-FDG radiotracers, including (124)I, (18)F-dihydroxyphenylalanine, and (68)Ga somatostatin analogs, is summarized. CONCLUSION: PET/CT is a valuable imaging test, in the appropriate clinical context, for the management of thyroid cancers.

A 7-Gene Biosignature for Ductal Carcinoma in situ of the Breast Identifies Subpopulations of HER2-positive Patients With Distinct Recurrence Rates After Breast-Conserving Surgery and Radiation Therapy.

PURPOSE: A subpopulation of women with ductal carcinoma in situ (DCIS) remains at risk for in-breast recurrence (IBR) following breast-conserving surgery (BCS) and radiation therapy (RT). The NSABP B-43 trial evaluated the role of concurrent RT and trastuzumab in patients with HER2-positive DCIS but did not reach the prespecified endpoint. We hypothesized that a 7-gene biosignature (DCISionRT) with its Residual Risk subtype (RRt) could identify 2 groups of HER2(3+) patients with significantly different IBR risks after BCS plus RT. PATIENTS AND METHODS: All patients with HER2(3+) DCIS (n = 178) treated with BCS plus RT were selected from a combined multinational patient cohort. Treatment decisions were neither randomized nor strictly rules-based. Biosignature testing was performed on all patients and stratified with previously defined groups: (1) Combined Low Risk group (DS ≤ 2.8) and Elevated Risk group (DS > 2.8) without RRt or (2) Residual Risk subtype. Kaplan-Meier analysis was used to compute IBR curves. RESULTS: Sixty-three percent of HER2(3+) patients (113/178) were classified into the Residual Risk subtype. These patients had significantly higher 10-year rates of IBR compared to the nonresidual risk group (16.2% vs. 1.6%, P = .01). The Residual Risk subtype had more nuclear grade 3 disease (87% vs. 63%, P < .001), but age, size, and grade were not associated with IBR rate (P = NS) on univariate and multivariable analysis. Only the Residual Risk group was associated with IBR (P = .05) in multivariate analysis. CONCLUSION: The 7-gene biosignature with RRt identified a subset of HER2(3+) patients with greater IBR rates following BCS and RT beyond traditional clinical and pathologic features. Consideration of therapies to reduce these elevated IBR rates should be evaluated, including the incorporation of HER2-targeted therapy.

Factors associated with local-regional recurrence after a negative sentinel node dissection: results of the ACOSOG Z0010 trial.

OBJECTIVE: To determine factors important in local-regional recurrence (LRR) in patients with negative sentinel lymph nodes (SLNs) by hematoxylin and eosin (H&E) staining. BACKGROUND: Z0010 was a prospective multicenter trial initiated in 1999 by the American College of Surgeons Oncology Group to evaluate occult disease in SLNs and bone marrow of early-stage breast cancer patients. Participants included women with biopsy-proven T1-2 breast cancer with clinically negative nodes, planned for lumpectomy and whole breast irradiation. METHODS: Women with clinical T1-2,N0,M0 disease underwent lumpectomy and SLN dissection. There was no axillary-specific treatment for H&E-negative SLNs, and clinicians were blinded to immunohistochemistry results. Systemic therapy was based on primary tumor factors. Univariable and multivariable analyses were performed to determine clinicopathologic factors associated with LRR. RESULTS: Of 5119 patients, 3904 (76.3%) had H&E-negative SLNs. Median age was 57 years (range 23-95). At median follow-up of 8.4 years, there were 127 local, 20 regional, and 134 distant recurrences. Factors associated with local-regional recurrence were hormone receptor-negative disease (P = 0.0004) and younger age (P = 0.047). In competing risk-regression models, hormone receptor-positive disease and use of chemotherapy were associated with reduction in local-regional recurrence. When local recurrence was included in the model as a time-dependent variable, older age, T2 disease, high tumor grade, and local recurrence were associated with reduced overall survival. CONCLUSIONS: Local-regional recurrences are rare in early-stage breast cancer patients with H&E-negative SLNs. Younger age and hormone receptor-negative disease are associated with higher event rates, and local recurrence is associated with reduced overall survival.

Safety and effectiveness of a novel nonpneumatic active compression device for treating breast cancer-related lymphedema: A multicenter randomized, crossover trial (NILE).

OBJECTIVE: Advanced pneumatic compression devices (APCDs) have been shown to be an effective intervention for lymphedema when used as part of a self-care maintenance treatment regimen. However, adherence to self-care has been poor, and APCDs require patients to be immobile during treatment. We evaluated the safety and efficacy of a novel nonpneumatic compression device (NPCD) for treating lymphedema vs an APCD. METHODS: A randomized, crossover head-to-head investigation was performed at five U.S. sites in 2021. The patients had been randomized to either the NPCD or a commercially available APCD. The patients used the randomly assigned initial device for 28 days with a 4-week washout period before a comparable 28-day use of the second device. RESULTS: Data from 50 adult women with unilateral breast cancer-related lymphedema were analyzed. Compared with the APCD, the NPCD was associated with a greater mean reduction in the limb edema volume (64.6% vs 27.7%; P < .001), significantly greater mean improvements in quality of life scores, greater adherence (95.6% vs 49.8%; P < .001), and greater satisfaction with the device (90% vs 14%; P < .001). The patients indicated that use of the NPCD facilitated exercise and was convenient for travel. No adverse events were reported. CONCLUSIONS: The results have shown that the novel NPCD is an effective maintenance treatment for reducing the limb volume in patients with breast cancer-related lymphedema. The NPCD device was more effective than an APCD and resulted in greater adherence to self-care interventions and greater patient satisfaction.

Combined 70- and 80-gene signatures identify tumors with genomically luminal biology responsive to neoadjuvant endocrine therapy and are prognostic of 5-year outcome in early-stage breast cancer.

BACKGROUND: As more patients with early-stage breast cancer receive neoadjuvant endocrine therapy (NET), there is a need for reliable biomarkers that can identify patients with HR+ HER2- tumors who are likely to benefit from NET. NBRST (NCT01479101) compared the prognostic value of the 70-gene risk classification and 80-gene molecular subtyping signatures with conventional pathological classification methods in response to neoadjuvant therapy. We evaluated the association of these signatures with clinical response and 5-year outcome of patients treated with NET. METHODS: 1091 patients with early-stage breast cancer scheduled to receive neoadjuvant therapy were prospectively enrolled into NBRST, and a sub-analysis of 67 patients treated with NET was performed. Patients received standard of care genomic testing using the 70-gene and 80-gene signatures and were treated with NET, per physician's discretion. The primary endpoint was pathologic partial response (pPR) and secondary endpoints were distant metastasis-free survival (DMFS) and overall survival (OS). Clinical benefit was defined as having a pPR or stable disease (SD) with NET. RESULTS: Overall, 94.4% of patients with genomically (g) Luminal A-Type (50.0% pPR and 44.4% SD) and 95.0% with Luminal B-Type tumors (55.0% pPR and 40.0% SD) exhibited clinical benefit. At 5 years, patients with gLuminal B tumors had significantly worse DMFS (75.6%, 95% CI 50.8-89.1) than patients with gLuminal A (91.1%; 95% CI 74.8-97.1; p = 0.047), with a similar trend for OS, albeit not significant (81.0%, 95% CI 56.9-92.4 and 91.1%, 95% CI 74.8-97.1, respectively; p = 0.13). CONCLUSIONS: Genomic assays offer a broader understanding of the underlying tumor biology, which adds precision to pathology as a preoperative risk classifier. Patients with 70-gene signature Low Risk, gLuminal A tumors treated with endocrine therapy alone have excellent 5-year outcomes. Most patients with genomically-defined Luminal A- and B-Type tumors respond well to NET, suggesting these patients may be safely treated with NET, while those with gLuminal B tumors will also require post-operative chemotherapy or CDK4/6 inhibitors to improve long-term outcomes. Overall, these findings demonstrate that genomic classification, defined by the combined 70- and 80-gene signatures, is associated with tumor response and prognostic of long-term outcomes.

Genomic Classification of HER2-Positive Patients With 80-Gene and 70-Gene Signatures Identifies Diversity in Clinical Outcomes With HER2-Targeted Neoadjuvant Therapy.

PURPOSE: The prospective Neoadjuvant Breast Registry Symphony Trial compared the 80-gene molecular subtyping signature with clinical assessment by immunohistochemistry and/or fluorescence in situ hybridization in predicting pathologic complete response (pCR) and 5-year outcomes in patients with early-stage breast cancer. METHODS: Standard-of-care neoadjuvant chemotherapy combined with trastuzumab or trastuzumab plus pertuzumab was given to patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (n = 295). pCR was the primary end point, with secondary end points of distant metastasis-free survival and overall survival at 5 years. RESULTS: Among clinically defined HER2-positive (cHER2) tumors, the 80-gene assay identified 29.5% (87 of 295) as Luminal-Type (cHER2/gLuminal), 14.9% (44 of 295) as Basal-Type (cHER2/gBasal), and 55.6% (164 of 295) as HER2-Type (cHER2/genomically classified as HER2 [gHER2]). Patients with cHER2/gHER2 tumors had a higher pCR rate (61.6%) compared with non-gHER2 tumors (26.7%; P < .001). Dual targeting for cHER2/gHER2 tumors yielded a higher pCR rate (75%) compared with those treated with single HER2-targeted therapy (54%; P = .006). For cHER2/gBasal tumors, the 42.9% pCR rate observed with dual targeting was not different from that with trastuzumab alone (46.4%; P = .830). Among those with cHER2/gBasal tumors, 5-year distant metastasis-free survival (68.6%; 95% CI, 49.1 to 81.9) was significantly worse than in patients with cHER2/gLuminal tumors (88.9%; 95% CI, 78.0 to 94.6) and cHER2/gHER2 tumors (87.4%; 95% CI, 80.2 to 92.2; P = .010), with similar corresponding overall survival differences. CONCLUSION: The 80-gene assay identified meaningful genomic diversity in patients with cHER2 disease. Patients with cHER2/gHER2 tumors, who benefitted most from dual HER2-targeted therapy, accounted for approximately half of the cHER2 cohort. Genomically Luminal tumors had low pCR rates but good 5-year outcomes. cHER2/gBasal tumors derived no benefit from dual therapy and had significantly worse 5-year prognosis; these patients merit special consideration in future trials.

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer.

Importance: National Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration. Objective: To examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making. Design, Setting, and Participants: Patients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022. Exposure: New and/or previous diagnosis of breast cancer. Main Outcomes and Measures: Disease management recommendations that were changed as a result of genetic testing results are reported. Results: Clinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]). Conclusions and Relevance: In this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

Distinct Neoadjuvant Chemotherapy Response and 5-Year Outcome in Patients With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Tumors That Reclassify as Basal-Type by the 80-Gene Signature.

PURPOSE: The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS: Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS: 80-GS reclassified 15% of ER+, HER2- tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION: Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

A novel automated assay for the rapid identification of metastatic breast carcinoma in sentinel lymph nodes.

BACKGROUND: The authors prospectively evaluated the performance of a proprietary molecular testing platform using one-step nucleic acid amplification (OSNA) for the detection of metastatic carcinoma in sentinel lymph nodes (SLNs) in a large multicenter trial and compared the OSNA results with the results from a detailed postoperative histopathologic evaluation (reference pathology) and from intraoperative imprint cytology (IC). METHODS: In total, 1044 SLN samples from 496 patients at 11 clinical sites were analyzed. Alternate 1-mm sections were subjected to either detailed histopathologic evaluation with hematoxylin and eosin and pancytokeratin immunostaining or the OSNA Breast Cancer System, which was calibrated to detect tumor deposits >0.2 mm by measuring cytokeratin 19 messenger RNA. At 7 sites, IC was performed before permanent section. The OSNA results were classified as negative (<250 copies/µL), micrometastases (from ≥250 to <5000 copies/µL), or macrometastases (≥5000 copies/µL). RESULTS: The sensitivity and specificity of the OSNA breast cancer system compared with reference pathology were 77.5% (95% confidence interval, 69.7%-84.2%) and 95.8% (95% confidence interval, 94.3%-97.0%), respectively, before discordant case analyses (DCA). Sensitivity and specificity after DCA were 82.7% and 97.7%, and final concordance was 95.8%. Performance for invasive lobular carcinoma demonstrated 88.2% sensitivity (95% confidence interval, 63.6%-98.5%) and 98.5% specificity (95% confidence interval, 92%-100%). The sensitivity of OSNA was significantly better than that of IC (80% vs 63%; P = .0229). CONCLUSIONS: The OSNA breast cancer system proved to be highly accurate for the detection of metastatic breast cancer in axillary SLNs. Sensitivity was comparable to that predicted for conventional postoperative histologic examination at 2-mm intervals and was significantly more sensitive than IC. Automation, semiquantitative results enabling the differentiation of macrometastasis and micrometastasis, and rapid results render the assay suitable for intraoperative and/or permanent evaluation of SLNs.

Intact Percutaneous Excision (IPEX) for Definitive Diagnosis of High-Risk Breast Lesions.

BACKGROUND: Open surgical excision (OSE) is generally recommended when image-guided core needle breast biopsy demonstrates a high-risk lesion (HRL). We evaluated intact percutaneous excision (IPEX) with standard radiologic and histologic criteria for definitive diagnosis of HRL, particularly atypical ductal hyperplasia (ADH).The primary goal was to confirm criteria associated with <2% risk for upgrade to carcinoma, equivalent to risk associated with BI-RADS 3 lesions, for which imaging surveillance is considered sufficient. METHODS: In an institutional review board-approved prospective trial, 1,170 patients recommended for breast biopsy at 25 institutions received IPEX with a vacuum- and radiofrequency-assisted device. ADH patients in whom the imaged lesion had been removed and the lesion adequately centered for definitive characterization were designated as the potential surgical avoidance population (PSAP) before OSE. Subsequent OSE specimen pathology was compared with IPEX findings. RESULTS: In 1,170 patients, 191 carcinomas and 83 (7%) HRL, including 32 ADH (3%), were diagnosed via IPEX. None of the 51 non-ADH HRL were upgraded to carcinoma on OSE (n = 24) or, if OSE was declined, on radiologic follow-up (n = 27). No ADH lesions meeting PSAP criteria (n = 10) were upgraded to carcinoma on OSE; 3 (14%) of 22 non-PSAP ADH lesions were upgraded to carcinoma on OSE. In summary, no upgrades to carcinoma were made in patients with non-ADH lesions who underwent IPEX or in ADH patients who had IPEX, met histologic and radiologic criteria, and underwent OSE. CONCLUSIONS: IPEX combined with straightforward histologic and radiologic criteria and imaging surveillance constitutes acceptable management of image-detected HRL, including ADH.

Definitive diagnosis for high-risk breast lesions without open surgical excision: the Intact Percutaneous Excision Trial (IPET).

BACKGROUND: Open surgical excision (OSE) is generally recommended when image-guided core-needle breast biopsy demonstrates a high-risk lesion (HRL). We evaluated intact percutaneous excision (IPEX) with standard radiologic and histologic criteria for definitive diagnosis of HRL, particularly atypical ductal hyperplasia (ADH). The primary aim is to confirm criteria associated with <2% risk for upgrade to carcinoma, equivalent to risk associated with Breast Imaging Reporting and Data System (BI-RADS) 3 lesions, for which imaging surveillance is considered sufficient. METHODS: In a prospective trial, 1,170 patients recommended for breast biopsy at 25 institutions received IPEX with a vacuum- and radiofrequency-assisted device. ADH patients in whom the imaged lesion had been removed and the lesion adequately centered for definitive characterization were designated as the potential surgical avoidance population (PSAP) before OSE. Subsequent OSE specimen pathology was compared with IPEX findings. RESULTS: In 1,170 patients, 191 carcinomas and 83 (7%) HRL, including 32 ADH (3%), were diagnosed via IPEX. None of the 51 non-ADH HRL were upgraded to carcinoma on OSE (n = 24) or, if OSE was declined, on radiologic follow-up (n = 27). No ADH lesions meeting PSAP criteria (n = 10) were upgraded to carcinoma on OSE; 3 (14%) of 22 non-PSAP ADH lesions were upgraded to carcinoma on OSE. In summary, no upgrades to carcinoma were made in patients with non-ADH lesions who underwent IPEX or in ADH patients who had IPEX, met histologic and radiologic criteria, and underwent OSE or follow-up. CONCLUSION: IPEX combined with straightforward histologic and radiologic criteria and imaging surveillance constitutes acceptable management of image-detected HRL, including ADH.

Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.

CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point. RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855.

Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer.

CONTEXT: Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. OBJECTIVE: To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. DESIGN, SETTING, AND PATIENTS: From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. INTERVENTIONS: All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. MAIN OUTCOME MEASURES: Overall survival (primary end point) and disease-free survival (a secondary end point). RESULTS: Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. CONCLUSION: Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003854.

Prognostic Risk Assessment and Prediction of Radiotherapy Benefit for Women with Ductal Carcinoma In Situ (DCIS) of the Breast, in a Randomized Clinical Trial (SweDCIS).

Prediction of radiotherapy (RT) benefit after breast-conserving surgery (BCS) for DCIS is crucial. The aim was to validate a biosignature, DCISionRT®, in the SweDCIS randomized trial. Women were randomly assigned to RT or not after BCS, between 1987 and 2000. Tumor blocks were collected, and slides were sent to PreludeDxTM for testing. In 504 women with complete data and negative margins, DCISionRT divided 52% women into Elevated (DS > 3) and 48% in Low (DS ≤ 3) Risk groups. In the Elevated Risk group, RT significantly decreased relative 10-year ipsilateral total recurrence (TotBE) and 10-year ipsilateral invasive recurrence (InvBE) rates, HR 0.32 and HR 0.24, with absolute decreases of 15.5% and 9.3%. In the Low Risk group, there were no significant risk differences observed with radiotherapy. Using a cutoff of DS > 3.0, the test was not predictive for RT benefit (p = 0.093); however, above DS > 2.8 RT benefit was greater for InvBE (interaction p = 0.038). Recurrences at 10 years without radiotherapy increased significantly per 5 DS units (TotBE HR:1.5 and InvBE HR:1.5). Continuous DS was prognostic for TotBE risk although categorical DS did not reach significance. Absolute 10-year TotBE and InvBE risks appear sufficiently different to indicate that DCISionRT can aid physicians in selecting individualized adjuvant DCIS treatment strategies. Further analyses are planned in combined cohorts to increase statistical power.

Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial.

BACKGROUND AND OBJECTIVE: Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. We now report local and regional recurrence information from the American College of Surgeons Oncology Group Z0011 trial. METHODS: American College of Surgeons Oncology Group Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H and E, who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated. RESULTS: There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the 2 groups were similar with respect to age, Bloom-Richardson score, estrogen receptor status, use of adjuvant systemic therapy, tumor type, T stage, and tumor size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared with a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the 2 groups. CONCLUSIONS: Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.