Intraoperative Ultrasound Guidance in Breast-Conserving Surgery Improves Cosmetic Outcomes and Patient Satisfaction: Results of a Multicenter Randomized Controlled Trial (COBALT).

BACKGROUND: Ultrasound-guided breast-conserving surgery (USS) results in a significant reduction in both margin involvement and excision volumes (COBALT trial). Objective. The aim of the present study was to determine whether USS also leads to improvements in cosmetic outcome and patient satisfaction when compared with standard palpation-guided surgery (PGS). METHODS: A total of 134 patients with T1­T2 invasive breast cancer were included in the COBALT trial (NTR2579) and randomized to either USS (65 patients) or PGS (69 patients). Cosmetic outcomes were assessed by a three-member panel using computerized software Breast Cancer Conservative Treatment cosmetic results (BCCT.- core) and by patient self-evaluation, including patient satisfaction. Time points for follow-up were 3, 6, and 12 months after surgery. Overall cosmetic outcome and patient satisfaction were scored on a 4-point Likert scale (excellent, good, fair, or poor), and outcomes were analyzed using a multilevel, mixed effect, proportional odds model for ordinal responses. RESULTS: Ultrasound-guided breast-conserving surgery achieved better cosmetic outcomes, with 20 % excellence overall and only 6 % rated as poor, whereas 14 % of PGS outcomes were rated excellent and 13 % as poor. USS also had consistently lower odds for worse cosmetic outcomes (odds ratio 0.55, p = 0.067) than PGS. The chance of having a worse outcome was significantly increased by a larger lumpectomy volume (ptrend = 0.002); a volume [40 cc showed odds 2.78-fold higher for a worse outcome than a volume B40 cc. USS resulted in higher patient satisfaction compared with PGS. CONCLUSION: Ultrasound-guided breast-conserving surgery achieved better overall cosmetic outcomes and patient satisfaction than PGS. Lumpectomy volumes[40 cc resulted in significantly worse cosmetic outcomes.

Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC).

Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1 matched controls. Controls, unscreened if<50 years, and screened with biennial mammography if ≥50 years, were matched on risk category (BRCA1, BRCA2, familial risk), year and age of diagnosis. Of 2,308 MRISC participants, breast cancer was detected in 93 (97 breast cancers), who received MRI <2 years before breast cancer diagnosis; 33 BRCA1 mutation carriers, 18 BRCA2 mutation carriers, and 42 with familial risk. MRISC patients had smaller (87% vs. 52%

Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicentre, randomised controlled trial.

BACKGROUND: Breast-conserving surgery for palpable breast cancer is associated with tumour-involved margins in up to 41% of cases and excessively large excision volumes. Ultrasound-guided surgery has the potential to resolve both of these problems, thereby improving surgical accuracy for palpable breast cancer. We aimed to compare ultrasound-guided surgery with the standard for palpable breast cancer-palpation-guided surgery-with respect to margin status and extent of healthy breast tissue resection. METHODS: In this randomised controlled trial, patients with palpable T1-T2 invasive breast cancer were recruited from six medical centres in the Netherlands between October, 2010, and March, 2012. Eligible participants were randomly assigned to either ultrasound-guided surgery or palpation-guided surgery in a 1:1 ratio via a computer-generated random sequence and were stratified by study centre. Patients and investigators were aware of treatment assignments. Primary outcomes were surgical margin involvement, need for additional treatment, and excess healthy tissue resection (defined with a calculated resection ratio derived from excision volume and tumour diameter). Data were analysed by intention to treat. This trial is registered at http://www.TrialRegister.nl, number NTR2579. FINDINGS: 134 patients were eligible for random allocation. Two (3%) of 65 patients allocated ultrasound-guided surgery had tumour-involved margins compared with 12 (17%) of 69 who were assigned palpation-guided surgery (difference 14%, 95% CI 4-25; p=0·0093). Seven (11%) patients who received ultrasound-guided surgery and 19 (28%) of those who received palpation-guided surgery required additional treatment (17%, 3-30; p=0·015). Ultrasound-guided surgery also resulted in smaller excision volumes (38 [SD 26] vs 57 [41] cm(3); difference 19 cm(3), 95% CI 7-31; p=0·002) and a reduced calculated resection ratio (1·0 [SD 0·5] vs 1·7 [1·2]; difference 0·7, 95% CI 0·4-1·0; p=0·0001) compared with palpation-guided surgery. INTERPRETATION: Compared with palpation-guided surgery, ultrasound-guided surgery can significantly lower the proportion of tumour-involved resection margins, thus reducing the need for re-excision, mastectomy, and radiotherapy boost. By achieving optimum resection volumes, ultrasound-guided surgery reduces unnecessary resection of healthy breast tissue and could contribute to improved cosmetic results and quality of life. FUNDING: Dutch Pink Ribbon Foundation, Osinga-Kluis Foundation, Toshiba Medical Systems.

[Breast-conserving surgery for breast cancer: still much to be gained]. / Mammasparende chirurgie voor borstkanker: er is nog winst te behalen.

OBJECTIVE: To conduct qualitative research into breast-conserving surgery for palpable and non-palpable breast tumours and the various methods of excising these, measured by the volume exised and surgical radicality. DESIGN: Retrospective, multicentre study. METHOD: The pathology reports from 726 patients who had undergone breast-conserving surgery for invasive breast cancer were reviewed for excision volume and radicality. Any excess resected breast tissue was expressed by a Calculated Resection Ratio (CRR) and calculated by dividing the volume of the surgical specimen by the tumour volume plus an ideal 1-cm-margin of tumour-free breast tissue. A CRR of 1.0 meant that the volume excised was ideal; a CRR of 2.0 meant that twice the necessary amount of tissue had been removed. RESULTS: Of all the 726 tumours, 72% appeared to be palpable. The median CRR in this group was 2.2 (range: 0.1 - 43.0) and the percentage of tumour-involved margins (irradicality) was 22.5%. Of all the non-palpable tumour (n = 201) excisions, 58% had been guided by wire-localisation, 26% by ultrasonography, and 16% by ROLL (Radio-guided Occult Lesion Localization). The CRRs were 2.8, 3.2 and 3.8, respectively (p < 0.05). Ultrasound-guided surgery resulted in the lowest rate of tumour-involved margins (ultrasound-guided: 3.8%, wire-guided localisation: 21.4%, ROLL: 25.0% (p = 0.05)). CONCLUSION: Breast-conserving surgery is associated with an average of a 2 to 4-fold removal of excessive tissue. Nevertheless, 1 out of 5 excisions are not radical. Ultrasound-guided surgery for non-palpable breast cancer is the most effective method for achieving radical excision. A multicentre, prospective, randomised trial has been started to assess whether ultrasound-guided lumpectomy for palpable breast cancer can lead to optimisation of the excision volume and radicality.

Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening-MRISC, MARIBS, and Canadian studies combined.

BACKGROUND: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. METHODS: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. RESULTS: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. CONCLUSIONS: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. IMPACT: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.

[Ultrasonically guided breast-conserving surgery for palpable mammary tumours]. / Echogeleide borstsparende chirurgie voor palpabel mammacarcinoom.

Breast-conserving surgery for palpable mammary tumours is usually guided by palpation. It appears, however, that identifying tumour margins only by palpation can be problematic, resulting in less than optimal effectiveness of this type of operation. The use of ultrasonography is a simple and non-invasive way of facilitating real-time localisation of breast carcinoma during surgery so that a tumour can be excised with controlled precision. Ultrasound is used to localise the tumour prior to surgery; its location is subsequently marked on the skin. During tissue dissection, ultrasound can be used to inspect the location and depth of the tumour as well as determining whether the tumour's surrounding margins are sufficient, thereby preventing the unnecessary removal of healthy tissue. Ultrasound can be used again after the excision to verify that the tumour was indeed radically removed. The efficacy of ultrasonically guided surgery for palpable mammary tumours is currently being studied in a prospective, randomised, multicentre trial.

Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial).

BACKGROUND: Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life. METHODS/DESIGN: In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described. CONCLUSION: The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR): NTR2579.

BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study.

PURPOSE: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS: Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION: Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition.

In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study(MRISC), a non-randomized prospective multicenter study,women with high familial risk or a genetic predisposition for breast cancer were screened once a year by mammography and MRI and every 6 months with a clinical breast examination (CBE). The false-negative MR examinations were subject of this study and were retrospectively reviewed by two experienced radiologists. From November 1999 until March 2006, 2,157 women were eligible for study analyses. Ninety-seven malignant breast tumors were detected, including 19 DCIS (20%). In 22 patients with a malignant lesion, the MRI was assessed as BI-RADS 1 or 2. One patient was excluded because the examinations were not available for review. Forty-three percent (9/21) of the false-negative MR cases concerned pure ductal carcinoma in situ (DCIS) or DCIS with invasive foci, in eight of them no enhancement was seen at the review. In six patients the features of malignancy were missed or misinterpreted.Small lesion size (n = 3), extensive diffuse contrast enhancement of the breast parenchyma (n = 2),and a technically inadequate examination (n = 1) were other causes of the missed diagnosis. A major part of the false-negative MR diagnoses concerned non-enhancing DCIS, underlining the necessity of screening not only with MRI but also with mammography. Improvement of MRI scanning protocols may increase the detection rate of DCIS. The missed and misinterpreted cases are reflecting the learning curve of a multicenter study.