PURPOSE:Current understanding of the interaction between radiation therapy (RT) and tumor-infiltrating lymphocytes (TILs) is limited. We investigated the impact of preoperative accelerated partial breast irradiation (PAPBI) on TILs in early-stage breast cancer patients. In addition, we evaluated whether baseline TILs were associated with pathologic response to RT. METHODS AND MATERIALS:In the prospective PAPBI trial, early-stage breast cancer patients received preoperative RT (10 × 4 or 5 × 6 Gy), followed by a wide local excision after 6 weeks. Matched control patients who underwent postoperative RT were retrospectively collected for validation. Stromal TILs (sTILs) were manually scored on hematoxylin- and eosin-stained slides from diagnostic biopsy and resection specimens, following established guidelines. Baseline differences in sTILs between patients with and without a pathologic complete response (pCR) were analyzed using the Mann-Whitney U test, and longitudinal changes in sTILs were evaluated with a linear mixed model. RESULTS:A total of 72 PAPBI patients and 68 matched controls were included. In the PAPBI cohort, baseline sTILs were generally low, with a median of 2% (IQR, 1%-2%). Eight patients (11%) achieved a pCR, and these patients had significantly higher baseline sTILs compared with patients without a pCR (P = .021). Among the 64 PAPBI patients with evaluable preirradiation and postirradiation samples, a minimal, nonsignificant increase in sTILs was observed following RT. Control patients had similarly low baseline sTILs (median, 2%; IQR, 1%-2%), with no significant changes over time. CONCLUSIONS:In this cohort of early-stage breast cancer patients receiving preoperative partial breast irradiation, longitudinal assessment showed minimal changes in sTILs after RT. In patients who achieved a pCR, we observed significantly higher baseline sTILs compared with those without a pCR.

INTRODUCTION:While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database. PATIENTS AND METHODS:A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations. Treatments included BRAF/MEK inhibitor combination therapy (BRAFi/MEKi) and the respective monotherapies. Clinical outcomes concerning overall response rate (ORR), progression-free (PFS), and overall survival (OS) were collected. RESULTS:Included patients had a median age of 65 years (range 20-93), 101 (71 %) were male. Most patients (n = 92, 64 %) received BRAFi/MEKi, 42 (29 %) BRAFi monotherapy, and 9 (6 %) MEKi monotherapy. The ORR was 35 % and higher in V600-nonE/K (45 %) than non-V600 melanomas (26 %, p = 0.025). Median duration of response was similar, with 8.2 months (range 2.9-53.1 +) for V600-nonE/K and 7.4 months (range 0.8-73.8 +) for non-V600. Combination therapy achieved best results in both groups, however, differences between V600-nonE/K and non-V600mutation were only found in ORR (51 % vs. 33 %, p = 0,11) and median PFS (6.5 vs. 3.2 months, p = 0.01). Patients with the longest PFS (> 50 months) had V600D/R, V600_K601D/E/N or K601E/N-, L597V/S/R/Q/P/K- mutations. OS was similar in both groups (16.1 vs. 11.7 months, p = 0.96). Of note, in non-V600 melanomas MEKi monotherapy revealed similar response rates as combination treatment (ORR 33 %, PFS 3 months); however, median OS was shorter (6.6 months, p = 0.02). CONCLUSIONS:This updated analysis reinforces the benefit of BRAFi/MEKi therapy in rare BRAF mutations. A database for ongoing data collection was developed and is available at https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen.

Ductal carcinoma in situ (DCIS) may progress to ipsilateral invasive breast cancer (iIBC), but often never will. Because DCIS is treated as early breast cancer, many women with harmless DCIS face overtreatment. To identify features associated with progression, we developed an artificial intelligence-based DCIS morphometric analysis pipeline (AIDmap) on hematoxylin-eosin-stained (H&E) tissue sections. We analyzed 689 digitized H&Es of pure primary DCIS of which 226 were diagnosed with subsequent iIBC and 463 were not. The distribution of 15 duct morphological measurements was summarized in 55 morphometric variables. A ridge regression classifier with cross validation predicted 5-years-free of iIBC with an area-under the curve of 0.67 (95% CI 0.57–0.77). A combined clinical-morphometric signature, characterized by small-sized ducts, a low number of cells and a low DCIS/stroma ratio, was associated with outcome (HR = 0.56; 95% CI 0.28–0.78). AIDmap has potential to identify harmless DCIS that may not need treatment.

Purpose: Axillary lymph node staging techniques after primary systemic therapy (PST) show low false negative rates, stimulating the omission of axillary lymph node dissection (ALND). Breast cancer patients with extensive nodal disease are underreported in studies on response-guided axillary treatment. In this study, we present the oncologic outcome of breast cancer patients with >= 4 involved axillary lymph nodes treated according to the MARI-protocol. Methods: This prospective single arm registration study included breast cancer patients with extensive nodal disease defined as >= 4 involved axillary lymph nodes on FDG-PET/CT pre-PST between July 2014 and December 2021. After PST, the marked (MARI) lymph node was excised. Patients with a pathologic complete response (pCR) of the MARI node (ypN0) received locoregional radiation treatment (RT). In patients with residual disease of the MARI node (ypN+), ALND was performed followed by RT. Primary endpoint was axillary recurrence rate. Secondary endpoints were invasive disease-free survival (DFS) and overall survival (OS). Results: In total, 218 patients were registered of which 39 % of patients also had extra-axillary nodal disease. Median (IQR) age was 50 (42-57) years. After PST 47 % of patients (103/218) had ypN0, whereas 53 % of patients (115/218) had ypN+. After a median follow up of 44 (26-62) months, axillary recurrence rate was 2.9 % (n = 3) in the ypN0 group and 3.5 % (n = 4) in the ypN + group. Five-year invasive DFS and OS were respectively 89 % (95 % CI 83 %-96 %) and 95 % (95 % CI 91 %-99 %) in ypN0 patients. Conclusion: Omission of ALND after PST in breast cancer patients with extensive nodal involvement who achieve pCR of the MARI node is associated with excellent five-year oncologic outcome.

Importance:Most patients with clinically node-positive (cN+) breast cancer receive primary systemic treatment (PST) followed by axillary lymph node dissection (ALND) and/or locoregional radiation (RT). The necessity of axillary treatment in patients achieving nodal pathologic complete response (pCR) after PST remains uncertain. Objective:To assess oncologic outcomes of response-guided axillary treatment determined by marking the axillary lymph node with a radioactive iodine seed (MARI) in patients with cN+ breast cancer who experience pCR after PST. Design, Setting, and Participants:This cohort study was conducted at a single center including patients with breast cancer with 3 or fewer axillary lymph nodes on fluorodeoxyglucose positron emission tomography-computed tomography who were treated according to the MARI protocol from July 2014 to December 2021. Patients with intramammary or periclavicular lymph node involvement were excluded. Median (IQR) follow-up was 49 (32-70) months. Data were analyzed from March to June 2025. Exposure:After PST, the MARI-marked lymph node was excised. Patients with pCR of the MARI node (ypN0) received no further axillary treatment, whereas patients with residual disease (ypN+) received locoregional radiation therapy. Main Outcomes and Measures:The primary outcome measure was axillary recurrence rate. The secondary outcome measures were 5-year invasive disease-free survival (iDFS) and overall survival (OS). Results:In total, 350 patients (median [IQR] age, 49 [41-56] years) were included and analyzed; of these, 135 (39%) had ypN0 and received no further axillary treatment. The remaining 215 patients with ypN+ (61%) received RT. After a median (IQR) follow-up of 49 (32-70) months, axillary recurrence rate was 0.7% (n = 1; 95% CI, 0.04%-4.1%) in patients with ypN0 and 2.3% (n = 7; 95% CI, 1.0%-5.3%) in patients with ypN+. In patients with ypN0, the 5-year iDFS was 93% (95% CI, 88%-98%) and the OS was 98% (95% CI, 95%-100%); in patients with ypN+, iDFS was 87% (95% CI, 82%-93%) and OS, 93% (95% CI, 89%-97%). Conclusions and Relevance:This cohort study found that response-guided axillary treatment, using the MARI protocol, in patients with limited nodal disease who received PST was associated with a very low risk of axillary recurrence and should be considered to protect patients from axillary overtreatment.

Abstract Background Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296–2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA), L. E. Elshof et al., Eur J Cancer, 51, 1497–510, 2015). Low-risk is defined as grade I or II DCIS. Because DCIS grade is a major eligibility criteria in these trials, it would be very helpful to assess DCIS grade on mammography, informed by grade assessed on DCIS histopathology in pre-surgery biopsies, since surgery will not be performed on a significant number of patients participating in these trials. Objective To assess the performance and clinical utility of a convolutional neural network (CNN) in discriminating high-risk (grade III) DCIS and/or Invasive Breast Cancer (IBC) from low-risk (grade I/II) DCIS based on mammographic features. We explored whether the CNN could be used as a decision support tool, from excluding high-risk patients for active surveillance. Methods In this single centre retrospective study, 464 patients diagnosed with DCIS based on pre-surgery biopsy between 2000 and 2014 were included. The collection of mammography images was partitioned on a patient-level into two subsets, one for training containing 80% of cases (371 cases, 681 images) and 20% (93 cases, 173 images) for testing. A deep learning model based on the U-Net CNN was trained and validated on 681 two-dimensional mammograms. Classification performance was assessed with the Area Under the Curve (AUC) receiver operating characteristic and predictive values on the test set for predicting high risk DCIS-and high-risk DCIS and/ or IBC from low-risk DCIS. Results When classifying DCIS as high-risk, the deep learning network achieved a Positive Predictive Value (PPV) of 0.40, Negative Predictive Value (NPV) of 0.91 and an AUC of 0.72 on the test dataset. For distinguishing high-risk and/or upstaged DCIS (occult invasive breast cancer) from low-risk DCIS a PPV of 0.80, a NPV of 0.84 and an AUC of 0.76 were achieved. Conclusion For both scenarios (DCIS grade I/II vs. III, DCIS grade I/II vs. III and/or IBC) AUCs were high, 0.72 and 0.76, respectively, concluding that our convolutional neural network can discriminate low-grade from high-grade DCIS.

BackgroundIn the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported.Materials and methodsWe studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models.ResultsWith a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status.ConclusionssTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Background: Axillary lymph node staging techniques (e.g., sentinel lymph node biopsy, MARI = Marking Axillary lymph nodes with Radioactive Iodine seeds, and TAD = targeted axillary dissection) after primary systemic therapy (PST) are associated with low false negative rates. This observation has stimulated the use of tailored axillary treatment, including the omission of axillary lymph node dissection (ALND). However, robust data on the oncologic outcomes following tailored axillary treatment after PST are lacking, especially in patients with extensive nodal disease. In this study, we present the axillary recurrence rate, disease free survival and overall survival of node positive breast cancer patients with >3 suspicious axillary lymph nodes treated according to the MARI-protocol.

Supplementary Materials and Methods

Neoadjuvant systemic treatment (NST) is increasingly part of tailored breast cancer treatment resulting in de-escalation of surgery and escalation of adjuvant systemic treatment for triple-negative (TN) and HER2+ patients with residual disease. It is questionable whether surgical resection contributes to local control in patients with pathologic complete response (pCR) after NST. However, current imaging and biopsy modalities aiming to detect pCR are not accurate enough. To gain more insight in the reason for this lack of accuracy, an in-depth analysis of the pathology results of the patients participating in the MICRA trial was performed. In the MICRA trial, patients with a complete or partial response on MRI after NST underwent ultra sound guided post-NST 14G biopsies followed by surgical resection of the original tumor area. In the current study, pathology reports of the biopsies and surgical specimen were further analyzed and comparisons between molecular subtypes were made. Primary outcome was the extent of missed residual invasive disease. In total, pathology reports of 167 patients participating in the MICRA trial were analyzed of which 69 had residual invasive disease in the surgical specimen. Median size of residual invasive disease in the surgical specimen varied between subtypes (p-value <0.001). In 27 of 65 patients with residual invasive disease and representative biopsies, this was missed by biopsies (FNR 41.5%). In hormone receptor positive (HR+)/HER2- patients median size of missed residual invasive disease was 6.5 mm (IQR 2.5 – 15.5), in HR+/HER2+ patients 7.0 mm (IQR 2.5 – 8.0), in HR-/HER2+ patients 4.0 mm (IQR 1.5 – 8.5) and in TN patients 4.0 mm (IQR 1.3 – 10.3). Notably, in all subtypes there were patients with residual invasive disease larger than 5 mm that was missed with biopsies. Since adjuvant systemic therapy for TN and HER2+ patients results in survival benefit for non-pCR patients, any residual invasive disease after NST should be detected. As post-NST biopsies do not accurately detect the often limited residual invasive disease in TN and HER2+ patients it is time to reconsider further surgical de-escalation strategies of the breast in these patients.

In clinically node-positive (cN+) breast cancer patients, evidence supporting response-guided treatment after neoadjuvant systemic therapy (NST) instead of axillary lymph node dissection (ALND) is increasing, but follow-up results are lacking. We assessed three-year axillary recurrence-free interval (aRFI) in cN+ patients with response-adjusted axillary treatment according to the ‘Marking Axillary lymph nodes with Radioactive Iodine seeds’ (MARI)-protocol. We retrospectively assessed all stage II–III cytologically proven cN+ breast cancer patients who underwent the MARI-protocol between July 2014 and November 2018. Pre-NST axillary staging with FDG-PET/CT (less- or more than four suspicious axillary nodes; cALN < 4 or cALN ≥ 4) and post-NST pathological axillary response measured in the pre-NST largest tumor-positive axillary lymph node marked with an iodine seed (MARI-node; ypMARI-neg or ypMARI-pos) determined axillary treatment: no further treatment (cALN < 4, ypMARI-neg), axillary radiotherapy (ART) (cALN < 4, ypMARI-pos and cALN ≥ 4, ypMARI-neg) or ALND plus ART (cALN ≥ 4, ypMARI-pos). Of 272 women included, the MARI-node was tumor-negative in 56 (32%) of 174 cALN < 4 patients and 43 (44%) of 98 cALN ≥ 4 patients. According to protocol, 56 (21%) patients received no further axillary treatment, 161 (59%) received ART and 55 (20%) received ALND plus ART. Median follow-up was 3.0 years (IQR 1.9–4.1). Five patients (one no further treatment, four ART) had axillary metastases. Three-year aRFI was 98% (95% CI 96–100). The overall recurrence risk remained highest for patients with ALND (HR 4.36; 95% CI 0.95–20.04, p = 0.059). De-escalation of axillary treatment according to the MARI-protocol prevented ALND in 80% of cN+ patients with an excellent three-year aRFI of 98%.

PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population–based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72–8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17–4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31–9.64), and absence of calcifications (OR 3.19; 95% CI 1.34–7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09–6.89) on pre-NST biopsy were significantly associated with DCIS response. As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

Background: Ductal Carcinoma in situ (DCIS) is considered a potential precursor of invasive breast cancer (BC) and is treated by mastectomy or breast conserving surgery (BCS) often supplemented with radiotherapy (RT). This study aimed to assess the long-term risk of ipsilateral subsequent in situ and invasive lesions after a diagnosis of primary DCIS and the association with initial DCIS treatment.

Background: More than one-third of clinically node positive (cN+) breast cancer (BC) patients currently show a pathologic complete response (pCR) of the axilla after neoadjuvant systemic therapy (NST). In patients with pCR, axillary lymph node dissection (ALND) is considered as overtreatment. The MARI procedure (Marking Axillary lymph nodes with Radioactive Iodine seeds) combined with pre-NST FDG-PET/CT (MARI protocol) is an accurate method to restage the axilla after NST. Here, we present 3-year follow-up results of BC patients treated according to the MARI protocol.

Purpose For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. Methods Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff’s alpha (KA) and Gwet’s AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. Results Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05–6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35–5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34–10.23) were independently associated with a higher iIBC risk. Conclusions Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

PURPOSE:BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited.METHODS:In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed.RESULTS:Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma.CONCLUSION:Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

Abstract Background An important advantage of neoadjuvant systemic therapy (NST) in breast cancer patients is down-sizing of the primary tumor. However, many patients with T3 tumors are treated with mastectomy regardless of response to NST. In this study, we evaluated predictive characteristics for positive margins and local control in T3 breast cancer patients who underwent breast-conserving therapy (BCT) after NST. Methods This single institution study included all clinical T3 breast cancer patients (determined by contrast-enhanced magnetic resonance imaging [MRI]) who underwent breast conserving surgery (BCS) after NST between 2000-2015. Clinical T3 was defined as a breast tumor >50mm on MRI pre-NST. Patient, tumor and treatment characteristics were recorded, as well as response on MRI and final pathology. The local recurrence probability was estimated with the Kaplan-Meier method. Predictive characteristics for positive margins in patients undergoing BCS were analyzed using Fishers exact test. Results In total, 115 T3 patients were identified. Patient, tumor and MRI findings are presenting in the table. Median tumor size was 60 mm on MRI pre-NST (range 51-120 mm) and 4 mm after NST (range 0-58 mm). Overall pathologic complete response was 19%: 5% in HR+/HER2- patients, 32% in HR-/HER2+ patients and 40% in TN patients. After initial BCS, 73 patients had negative margins (63.5%), 18 focally positive margins (15.7%) and 24 more than focally positive margins (20.9%). Patients with HR+/HER2- tumors (52%) were more likely to have positive margins than patients with HR-/HER2+ and TN tumors (21% and 19%, p=0.002). In addition, positive margins rate was higher in patients with lobular carcinoma compared to patients with ductal carcinoma (57 vs 32%, p=0.031). Presence of non-mass enhancement on pre-NST MRI was predictive for positive margins (52% in patients with and 25% in patients without non-mass enhancement, p=0.003). Of patient with positive margins, 15 underwent radiotherapy with boost, 6 underwent re-excision and 21 underwent mastectomy. Finally, 94/115 patients were treated with BCT (82%). Of these patients, two had a local recurrence after a median follow-up of 6.5 years (6-year local recurrence probability 2.6% (95%-CI 0-7%). Conclusion In this series, BCT after NST was successful in 82% of patients with T3 breast cancer and local control in this group was excellent. The positive margin rate after BCS was higher in patients with HR+ tumors, lobular carcinoma and tumors with non-mass enhancement on MRI pre-NST. BCT should always be considered in T3 cancers after NST. CharacteristicTotal (n=115)Positive margins (focally+ >focally), n=42(%)p-valueHistology 0.031Ductal9229(32) Lobular2313(57) Subtype 0.002HR+/HER2-6132(52) HER2+347(21) TN203(15) MRI morphology of mass pre-NST 0.948Unifocal288(29) Multifocal4012(33) Multicentric134(31) Only non-mass enhancement34 MRI non-mass enhancement before NST 0.003Absent6516(25) Present5026(52) MRI response after NST 0.952rCR5218(35) non-rCR6221(38) Missing1 Citation Format: van der Noordaa ME, Vrancken Peeters M-JM, Ioan I, Loo CE, van Urk J, van Werkhoven E, Voorthuis R, Wiersma T, Groen E, Rutgers ET, van Duijnhoven FH. Breast conserving therapy after neoadjuvant systemic therapy in patients with T3 breast cancer is feasible [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-13-02.