De-ESCAlating RadioTherapy in breast cancer patients with pathologic complete response to neoadjuvant systemic therapy: DESCARTES study.

PURPOSE: Neoadjuvant systemic therapy (NST) is increasingly used in breast cancer patients and depending on subtype, 10-89% of patients will attain pathologic complete response (pCR). In patients with pCR, risk of local recurrence (LR) after breast conserving therapy is low. Although adjuvant radiotherapy after breast conserving surgery (BCS) reduces LR further in these patients, it may not contribute to overall survival. However, radiotherapy may cause early and late toxicity. The aim of this study is to show that omission of adjuvant radiotherapy in patients with a pCR after NST will result in acceptable low LR rates and good quality of life. METHODS: The DESCARTES study is a prospective, multicenter, single arm study. Radiotherapy will be omitted in cT1-2N0 patients (all subtypes) who achieve a pCR of the breast and lymph nodes after NST followed by BCS plus sentinel node procedure. A pCR is defined as ypT0N0 (i.e. no residual tumor cells detected). Primary endpoint is the 5-year LR rate, which is expected to be 4% and deemed acceptable if less than 6%. In total, 595 patients are needed to achieve a power of 80% (one-side alpha of 0.05). Secondary outcomes include quality of life, Cancer Worry Scale, disease specific and overall survival. Projected accrual is five years. CONCLUSION: This study bridges the knowledge gap regarding LR rates when adjuvant radiotherapy is omitted in cT1-2N0 patients achieving pCR after NST. If the results are positive, radiotherapy may be safely omitted in selected breast cancer patients with a pCR after NST. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov on June 13th 2022 (NCT05416164). Protocol version 5.1 (15-03-2022).

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations: First Results from the TESTBREAST Study.

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.

70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.

BACKGROUND: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. METHODS: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing. FINDINGS: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]). INTERPRETATION: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. FUNDING: European Commission Sixth Framework Programme.

Risk of heart failure after systemic treatment for early breast cancer: results of a cohort study.

PURPOSE: Anthracyclines and trastuzumab can increase the risk of heart failure (HF), but long-term cardiotoxicity data in breast cancer (BC) patients treated at younger ages are limited. Furthermore, it is unknown whether aromatase inhibitors are associated with HF risk. METHODS: HF risk was studied in a multicenter cohort of BC survivors treated during 2000-2009, at age < 61 years. Information on treatment and cardiovascular disease incidence was collected through medical records, general practitioners and cardiologists. Analyses included multivariable Cox regression and cumulative incidence curves. RESULTS: In total, 10,209 women with a median age at BC diagnosis of 50.3 years and a median follow-up of 8.9 years were enrolled in the study. Anthracycline-based chemotherapy was associated with HF (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.41-3.39) and risk increased with increasing cumulative anthracycline dose. For trastuzumab, HF risk was highest within the first 2 years after treatment (HR0-2 years: 13.06, 95% CI 5.70-29.92) and decreased thereafter (HR2-4 years: 4.84, 95% CI 1.99-11.75 and HR≥4 years: 0.64, 95% CI 0.23-1.81). The 10-year cumulative incidence of HF was 4.8% (95% CI 3.2-6.8) among patients treated with anthracyclines and trastuzumab. One-third of patients who developed HF after trastuzumab had long-term impaired cardiac function. Patients treated with aromatase inhibitors alone also had higher HF risk (HR 2.18, 95% CI 1.24-3.82) compared to patients not receiving endocrine therapy. CONCLUSIONS: Our results stress the importance of considering anthracycline-free regimens in BC patients who need trastuzumab-containing treatment. The association between aromatase inhibitors and HF needs confirmation.

Breast-Conserving Therapy in Patients with cT3 Breast Cancer with Good Response to Neoadjuvant Systemic Therapy Results in Excellent Local Control: A Comprehensive Cancer Center Experience.

BACKGROUND: Many cT3 breast cancer patients are treated with mastectomy, regardless of response to neoadjuvant systemic therapy (NST). We evaluated local control of cT3 patients undergoing breast-conserving therapy (BCT) based on magnetic resonance imaging (MRI) evaluation post-NST. In addition, we analyzed predictive characteristics for positive margins after breast-conserving surgery (BCS). METHODS: All cT3 breast cancer patients who underwent BCS after NST between 2002 and 2015 at the Netherlands Cancer Institute were included. Local recurrence-free interval (LRFI) was estimated using the Kaplan-Meier method, and predictors for positive margins were analyzed using univariable analysis and multivariable logistic regression. RESULTS: Of 114 patients undergoing BCS post-NST, 75 had negative margins, 16 had focally positive margins, and 23 had positive margins. Of those with (focally) positive margins, 12 underwent radiotherapy, 6 underwent re-excision, and 21 underwent mastectomy. Finally, 93/114 patients were treated with BCT (82%), with an LRFI of 95.9% (95% confidence interval [CI] 91.5-100%) after a median follow-up of 7 years. Predictors for positive margins in univariable analysis were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype, lobular carcinoma, and non-mass enhancement (NME) on pre-NST MRI. MRI response was not correlated to positive margins. In multivariable regression, the odds of positive margins were decreased in patients with HER2-positive (HER2+; odds ratio [OR] 0.27, 95% CI 0.10-0.73; p = 0.01) and TN tumors (OR 0.17, 95% CI 0.03-0.82; p = 0.028). A trend toward positive margins was observed in patients with NME (OR 2.38, 95% CI 0.98-5.77; p = 0.055). CONCLUSION: BCT could be performed in 82% of cT3 patients in whom BCT appeared feasible on post-NST MRI. Local control in these patients was excellent. In those patients with HR+/HER2- tumors, NME on MRI, or invasive lobular carcinoma, the risk of positive margins should be considered preoperatively.

MRI versus mammography for breast cancer screening in women with familial risk (FaMRIsc): a multicentre, randomised, controlled trial.

BACKGROUND: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. METHODS: In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30-55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. FINDINGS: Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5-14] vs 17 mm [13-22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). INTERPRETATION: MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. FUNDING: Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

Prognostic Impact of Breast-Conserving Therapy Versus Mastectomy of BRCA1/2 Mutation Carriers Compared With Noncarriers in a Consecutive Series of Young Breast Cancer Patients.

OBJECTIVE: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers. SUMMARY OF BACKGROUND DATA: Although breast-conserving therapy (breast-conserving surgery followed by radiotherapy) has been associated with more local recurrences than mastectomy, no differences in overall survival have been found in randomized trials performed in the general breast cancer population. Whether breast-conservation can be safely offered to BRCA1/2 mutation carriers is debatable. METHODS: The study comprised a cohort of women with invasive breast cancer diagnosed <50 years and treated between 1970 and 2003 in 10 Dutch centers. Germline DNA for BRCA1/2 testing of most-prevalent mutations (covering ∼61%) was mainly derived from paraffin-blocks. Survival analyses were performed taking into account competing risks. RESULTS: In noncarriers (N = 5820), as well as in BRCA1 (N = 191) and BRCA2 (N = 70) mutation carriers, approximately half of the patients received breast-conserving therapy. Patients receiving mastectomy followed by radiotherapy had prognostically worse tumor characteristics and more often received systemic therapy. After adjustment for these potential confounders, patients who received breast-conserving therapy had a similar overall survival compared with patients who received mastectomy, both in noncarriers (hazard ratio [HR] = 0.95, confidence interval [CI] = 0.85-1.07, P = 0.41) and BRCA1 mutation carriers (HR = 0.80, CI = 0.42-1.51, P = 0.50). Numbers for BRCA2 were insufficient to draw conclusions. The rate of local recurrences after breast-conserving therapy did not differ between BRCA1 carriers (10-year risk = 7.3%) and noncarriers (10-year risk = 7.9%). CONCLUSION: Our results, together with the available literature, provide reassurance that breast-conserving therapy is a safe local treatment option to offer to BRCA1 mutation carriers with invasive breast cancer.

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.).

Internal Mammary Chain Sentinel Nodes in Early-Stage Breast Cancer Patients: Toward Selective Removal.

BACKGROUND: Removal of internal mammary chain sentinel nodes (IMCSNs) affects prognosis and treatment of breast cancer, and internal mammary chain radiotherapy (IMCRT) can improve survival for selected patients. This study aimed to determine the effect of IMCSN biopsy on recurrence-free survival (RFS) and overall survival (OS) and to identify predictive factors for IMCSN and distant metastasis. METHODS: Patients with IMCSNs were selected from a prospective database for the period 1999-2007. Lymphoscintigraphy was performed after intratumoral technetium-99 m injection, and all sentinel nodes were removed. Both RFS and OS were calculated for subgroups with tumor-positive, tumor-negative, or non-removed IMCSNs. Predictive factors were identified for tumor-positive IMCSNs and distant metastasis by regression analysis. RESULTS: For 287 (85%) of 336 patients, IMCSN biopsy was performed, and metastasis was detected in 38 patients (13%). The patients with tumor-positive IMCSNs had poorer OS than the patients with no IMCSN metastasis or non-removed IMCSNs (p = 0.002). These patients also had worse RFS due to distant metastasis (p = 0.002). Axillary metastasis was predictive for tumor-positive IMCSNs (positive predictive value, 38.5%). The predictive factors for distant metastasis were tumor-positive IMCSNs (hazard ratio [HR], 2.5), non-removed IMCSNs (HR, 2.3), tumor diameter greater than 1.5 cm (HR, 3.5), and age older than 65 years (HR, 3.1; reference, < 50 years). CONCLUSIONS: Patients with IMCSNs have worse survival due to distant metastasis. The clinically relevant predictive factor for distant metastasis is tumor larger than 1.5 cm. According to the authors' current protocol, IMCSN biopsy is performed for patients younger than 70 years who have a tumor larger than 1.5 cm, with the cardiotoxicity of the adjuvant IMCRT weighed against the survival benefit.

Sentinel lymph node nonvisualization after intratumoral radioisotope tracer injection in breast cancer is not associated with a higher nodal metastasis rate or worse outcomes.

BACKGROUND AND OBJECTIVES: Preoperative lymphoscintigraphy does not always visualize a sentinel lymph node (SLN). The study aim was to investigate whether persistent nonvisualization after additional single-photon emission computed tomography (SPECT)/CT or a second radiotracer injection in breast cancer patients is associated with nodal metastases or worse outcome due to potential understaging and consequently undertreatment. METHODS: Altogether 2042 consecutive SLN procedures were evaluated. All patients were clinically node-negative, underwent axillary ultrasound and fine-needle aspiration cytology (US/FNAC) of suspicious nodes. Lymphoscintigraphy was performed at 3 to 4 hours after intratumoral injection of 99mTc-nanocolloid. SPECT/CT or a reinjection was performed when initial lymphoscintigraphy showed nonvisualization. RESULTS: Persistent nonvisualization was seen in 170 of 2042 procedures (8.3%). The nodal metastasis rate was 16.0% vs 18.0% for procedures with nonvisualization vs SLN visualization, respectively (P = 0.593). The regional recurrence rate of tumor-negative SLN biopsy procedures was equal between the visualization (0.7%, 11 of 1535) vs nonvisualization (0.7%, 1 of 144) group. Median follow-up was 48 months. Distant-metastasis free interval and overall survival was not significantly different between both groups ( P = 0.164 and 0.208, respectively). CONCLUSIONS: Persistent nonvisualization after lymphoscintigraphy plus SPECT/CT or radiotracer reinjection is not associated with a higher nodal metastasis rate or worse long term outcome when preoperative US/FNAC is performed.

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer.

BACKGROUND: Improved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment. METHODS: We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970-2009. Analyses included proportional hazards models and general population comparisons. RESULTS: CVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93-1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9-17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6-2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07-5.69), emerging <5 years and remaining increased at least 10-15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01-14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy. CONCLUSIONS: Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

Cause-specific Mortality in a Population-based Cohort of 9799 Women Treated for Ductal Carcinoma In Situ.

OBJECTIVE: To assess cause-specific mortality in women treated for ductal carcinoma in situ (DCIS). BACKGROUND: From screening and treatment perspective, it is relevant to weigh the low breast cancer mortality after DCIS against mortality from other causes and expected mortality in the general population. METHODS: We conducted a population-based cohort study comprising 9799 Dutch women treated for primary DCIS between 1989 and 2004 and estimated standardized mortality ratios (SMRs). RESULTS: After a median follow up of 9.8 years, 1429 patients had died of whom 284 caused by breast cancer (2.9% of total cohort). DCIS patients <50 years experienced higher mortality compared with women in the general population (SMR 1.7; 95% confidence interval, CI: 1.4-2.0), whereas patients >50 had significantly lower mortality (SMR 0.9; 95% CI: 0.8-0.9). Overall, the risk of dying from general diseases and cancer other than breast cancer was lower than in the general population, whereas breast cancer mortality was increased. The SMR for breast cancer decreased from 7.5 (95% CI: 5.9-9.3) to 2.8 (95% CI: 2.4-3.2) for women aged <50 and >50 years, respectively. The cumulative breast cancer mortality 10 years after DCIS was 2.3% for women <50 years and 1.4% for women >50 years treated for DCIS between 1999 and 2004. CONCLUSIONS: DCIS patients >50 years had lower risk of dying from all causes combined compared with the general female population, which may reflect differences in health behavior. Women with DCIS had higher risk of dying from breast cancer than the general population, but absolute 10-year risks were low.

Current approach of the axilla in patients with early-stage breast cancer.

The surgical approach of the axilla in patients with early-stage breast cancer has witnessed considerable evolution during the past 25 years. The previously undisputed gold standard of axillary-lymph-node dissection for staging has now been replaced by sentinel-lymph-node biopsy for patients with clinically negative axilla. For selected patients with limited sentinel-lymph-node involvement, completion axillary-lymph-node dissection can be omitted or replaced by axillary radiotherapy, reducing morbidity. The clinical interest of axillary staging after neoadjuvant chemotherapy is increasing and this approach might contribute to morbidity reduction, and to the further tailoring of future systemic and locoregional treatment decisions by response assessment. Refinement of the sentinel-lymph-node biopsy technique might overcome the slightly impaired success rates in this setting. New techniques for lymphatic mapping attempt to further simplify the procedure. In view of the declining influence of axillary nodal status on adjuvant therapy decision-making, ongoing clinical trials will evaluate whether sentinel-lymph-node biopsy can be avoided altogether in selected patients.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

PURPOSE: For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. METHODS: In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. RESULTS: In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. CONCLUSIONS: This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

The method of detection of ductal carcinoma in situ has no therapeutic implications: results of a population-based cohort study.

BACKGROUND: Population screening with mammography has resulted in increased detection of ductal carcinoma in situ (DCIS). The aim of this population-based cohort study was to assess whether the method of detection should be considered when determining prognosis and treatment in women with DCIS. METHODS: This study includes 7042 women aged 49-75 years, who were surgically treated for primary DCIS between 1989 and 2004 in the Netherlands. We calculated cumulative incidences of ipsilateral and contralateral invasive breast cancer and all-cause mortality among women with screen-detected, interval, or non-screening-related DCIS, and assessed the association between method of detection and these outcomes, using multivariable Cox regression analyses. RESULTS: Compared with non-screening-related DCIS, women with screen-detected DCIS had a lower risk of developing ipsilateral invasive breast cancer (hazard ratio (HR) = 0.75, 95% CI = 0.59-0.96), but a similar risk of contralateral invasive breast cancer (HR = 0.86, 95% CI = 0.67-1.10). The absolute difference in risk of ipsilateral invasive breast cancer was 1% at 15 years. Screen detection was associated with lower all-cause mortality (HR = 0.85, 95% CI = 0.73-0.98); when we additionally accounted for the occurrence of invasive breast cancer the magnitude of this effect remained similar (HR = 0.86, 95% CI = 0.75-1.00). CONCLUSIONS: Screen detection was associated with lower risk of ipsilateral invasive breast cancer and all-cause mortality. However, the absolute difference in risk of ipsilateral invasive breast cancer was very low and the lower all-cause mortality associated with screen-detected and interval DCIS might be explained by a healthy-user effect. Therefore, our findings do not justify different treatment strategies for women with screen-detected, interval, or non-screening-related DCIS.

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Contribution of SPECT/CT for sentinel node localization in patients with ipsilateral breast cancer relapse.

BACKGROUND: In recent years repeat sentinel node (SN) biopsy has been proven to be feasible in local breast cancer recurrence (LBCR). However, in these patients SNs outside the ipsilateral axilla are frequently observed. This study evaluates the contribution of SPECT/CT for SN localization and surgical adjustment in LBCR patients. METHODS: SN biopsy was performed in 122 LBCR patients (median age 60.5 years, range 24-87), enrolled from August 2006 to July 2015. Median disease-free time lapse was 109.5 months (range 9-365). Axillary lymph node dissection (ALND) had previously been performed in 55 patients, SN biopsy in 44, both techniques in 13 and fine-needle aspiration in 10. Primary breast cancer treatment included radiotherapy in 104 patients (85.3 %) and chemotherapy in 40 (32.8 %). Preoperative lymphatic mapping, using planar scintigraphy (PS) and SPECT/CT included report of SN location according to lymph node territory. In case of a territorial PS-SPECT/CT mismatch, surgery was adjusted according to SPECT/CT findings. RESULTS: SPECT/CT SN visualization rate was higher than PS (53.3 % vs. 43.4 %, p n.s.) with, in total, 19 additional SN (118 vs. 99, p n.s.). PS-SPECT/CT territory mismatch, found in 60 % (39/65) of patients with SN visualization, led to surgical adjustment in 21.3 % (26/122) of patients. The SN procedure was finally performed in 104 patients resulting in a 65.7 % surgical retrieval rate with a total of 132 removed SNs (1.86/patient). SN metastases were found in 17/71 patients (23.9 %), in 16 of them (94 %) in ipsilateral basins outside the axilla or in the contralateral axilla. CONCLUSION: Using SPECT/CT there is a trend to visualize more SNs in LBCR, providing at the same time important anatomical information to adjust intraoperative SN procedures. The addition of SPECT/CT to the standard imaging protocol may lead to better staging mainly in patients presenting drainage outside the ipsilateral axilla.

Rapid genetic counseling and testing in newly diagnosed breast cancer: Patients' and health professionals' attitudes, experiences, and evaluation of effects on treatment decision making.

BACKGROUND: Rapid genetic counseling and testing (RGCT) in newly diagnosed high-risk breast cancer (BC) patients may influence surgical treatment decisions. To successfully integrate RGCT in practice, knowledge of professionals', and patients' attitudes toward RGCT is essential. METHODS: Between 2008 and 2010, we performed a randomized clinical trial evaluating the impact of RGCT. Attitudes toward and experience with RGCT were assessed in 265 patients (at diagnosis, 6- and 12-month follow-up) and 29 medical professionals (before and after the recruitment period). RESULTS: At 6-month follow-up, more patients who had been offered RGCT felt they had been actively involved in treatment decision-making than patients who had been offered usual care (67% vs 48%, P = 0.06). Patients who received DNA-test results before primary surgery reported more often that RGCT influenced treatment decisions than those who received results afterwards (P < 0.01). Eighty-seven percent felt that genetic counseling and testing (GCT) should preferably take place between diagnosis and surgery. Most professionals (72%) agreed that RGCT should be routinely offered to eligible patients. Most patients (74%) and professionals (85%) considered surgeons the most appropriate source for referral. CONCLUSIONS: RGCT is viewed as helpful for newly diagnosed high-risk BC patients in choosing their primary surgery and should be offered routinely by surgeons.

Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women.

PURPOSE: To assess the effect of different treatment strategies on the risk of subsequent invasive breast cancer (IBC) in women diagnosed with ductal carcinoma in situ (DCIS). METHODS: Up to 15-year cumulative incidences of ipsilateral IBC (iIBC) and contralateral IBC (cIBC) were assessed among a population-based cohort of 10,090 women treated for DCIS in the Netherlands between 1989 and 2004. Multivariable Cox regression analyses were used to evaluate associations of treatment with iIBC risk. RESULTS: Fifteen years after DCIS diagnosis, cumulative incidence of iIBC was 1.9 % after mastectomy, 8.8 % after BCS+RT, and 15.4 % after BCS alone. Patients treated with BCS alone had a higher iIBC risk than those treated with BCS+RT during the first 5 years after treatment. This difference was less pronounced for patients <50 years [hazard ratio (HR) 2.11, 95 % confidence interval (CI) 1.35-3.29 for women <50, and HR 4.44, 95 % CI 3.11-6.36 for women ≥50, P interaction  < 0.0001]. Beyond 5 years of follow-up, iIBC risk did not differ between patients treated with BCS+RT or BCS alone for women <50. Cumulative incidence of cIBC at 15 years was 6.4 %, compared to 3.4 % in the general population. CONCLUSIONS: We report an interaction of treatment with age and follow-up period on iIBC risk, indicating that the benefit of RT seems to be smaller among younger women, and stressing the importance of clinical studies with long follow-up. Finally, the low cIBC risk does not justify contralateral prophylactic mastectomies for many women with unilateral DCIS.

Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer : Intratumoral heterogeneity and DCIS or normal tissue components are unlikely to be the cause of discordance.

Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance.