In-breast Tumor Recurrence Research Articles

Comparison of Outcome between Invasive Lobular Carcinoma (ILC) and Invasive Ductal Carcinoma (IDC) Patients Treating with Breast Conserving Surgery (BCS) and Radical Dose of Intraoperative Electron Radiotherapy (IOERT)

Background: Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in genomic profile, clinicopathologic behavior, and response to treatment. Despite favorable profile, ILC is susceptible to recurrence. Thus, most of studies did not include ILC in intraoperative radiotherapy (IORT) trials or considered it as a cautionary criteria, especially in accelerated partial breast irradiation (APBI). Objectives: In this study, we compared treatment outcome between breast cancer patients with ILC and IDC treating with breast conserving surgery and intraoperative electron radiotherapy (IOERT). Methods: A total of 191 patients with early breast cancer treated with breast conserving surgery and IOERT were included in the study. This study compared outcome of 42 ILC patients with 135 IDC patients. Fourteen patients were mixed type. ILC was a suitable criterion, as well. Local recurrence and disease-free survival were endpoints of study. Results: Median follow-up was 23.17 month and 21.17 month for IDC and ILC, respectively. Univariate analysis was done according to age, pathologic, and biologic factors and multivariate analysis was according molecular subtype. There were 3 patients with local recurrence. Two patients were in the IDC group and another one was the ILC group. There was no significant difference between two groups. The 4-year disease-free survival (DFS) was 95.45% and 97.40% for ILC and IDC, respectively. Conclusions: In this study, there was no significant difference in in-breast tumor recurrence (IBTR) and DFS between two groups. It was seem lobular carcinoma can be used for APBI and it may be a suitable criterion as the IDC.

Concordance of Biomarkers and Tumor Location for in-Breast Tumor Recurrences in Early Stage Breast Cancer Patients Treated with Breast Conserving Surgery and Adjuvant RT

Patients with an in-breast tumor recurrence (IBTR) after breast-conserving therapy have a high risk of distant metastasis and disease-related mortality. Identifying clinical parameters that increase risk for recurrence after IBTR remains a challenge. Our purpose is to describe clinical and treatment parameters of primary and IBTRs that may predict decreased disease free survival after IBTR. Patients with stage 0-II breast cancer treated with lumpectomy and adjuvant radiation were identified from institutional databases of patients treated from 2003-2017 at our institution. Overall survival (OS), Disease free survival (DFS), and Local recurrence free survival (LRFS) were estimated using the Kaplan Meier method. We subsequently identified patients who experienced an isolated IBTR. Concordance of hormone receptor status and location of tumor from primary to recurrence was evaluated using chi-squared tests. The effect of clinical and treatment parameters with time interval to the first IBTR was evaluated using ANOVA. We identified 2217 patients who met eligibility criteria. The median follow-up (FU) was 44 months (IQR: 25.7 – 70.9). OS at 5-years was 97.7%, DFS was 96.1% and LRFS was 97.9%. The median time to IBTR was 33.8 months (IQR: 21 – 44). We identified 37 patients with isolated IBTR, 51.4% as DCIS, and 48.6% as invasive disease, of whom 83.3% had an in situ component. Radiotherapy information was available for 30 patients. Median whole-breast dose was 40.5Gy; 23 patients received a boost to the tumor bed, with the median dose with boost of 48Gy. In 80.6% of patients, hormone receptor status at recurrence was concordant with the primary tumor. ER and PR receptor status from primary to IBTR were highly associated (ER: χ2, p = 0.006; PR: χ2, p=0.001). There were no changes in HER2 status from primary to IBTR. There was a high level of concordance between quadrant of tumor from primary to IBTR (62.2% of IBTRs, χ2, p=0.008). Tumor size greater than 1.5 cm and endocrine therapy upfront were associated with longer interval to IBTR (ANOVA p=0.02, p=0.004, respectively). At the time of IBTR, 86.5% of patients underwent salvage surgery (43.2% bilateral mastectomy, 24.3% unilateral mastectomy, and 16.2% local excision), 21.6 % received chemotherapy, and 43.2% received endocrine therapy. DFS after IBTR was 81.1% (median FU = 25.5 months, IQR: 11.6 – 56.4) with 57% local, 14% regional and 29% distant recurrences after IBTR. DFS after IBTR was not associated with histology at initial presentation (p=0.4), concordance of biomarkers (p=0.8), concordance of tumor location (p=0.8), or presence of an in situ component with IBTR (p=0.9). Among patients with early stage breast cancer patients who had BCS treated with adjuvant RT, ER/PR status and quadrant are highly concordant from primary to IBTR. The overall recurrence rate in this modern series was low. There was no correlation between concordance of biomarkers and tumor location and the presence of an in situ component at recurrence with improved DFS after IBTR.

Local Recurrence Rates for Early Stage Breast Cancer Treated with Breast Conservation and Single Fraction IntraOperative Electron Radiation Therapy ( IOERT) at a Community Hospital

Patients with early stage breast cancer are offered adjuvant breast irradiation after lumpectomy to reduce the likelihood of recurrence . This is usually in the form of whole breast irradiation. However, large multi-institutional randomized data show that partial breast irradiation using single fraction intraoperative electron radiotherapy ( IOERT) may be safe and appropriate in a subset of patients with early stage disease. Our goal was to prospectively determine the local in-breast tumor recurrence ( IBTR) rate at a single community center using IOERT. Patients with early stage breast cancer treated with breast conservation +/- SLNB and single fraction IOERT were enrolled prospectively in an in-house trial . Patient demographics , clinical/ pathologic staging , tumor histology , grade and receptor status were recorded. Patient eligibility included women age >/=40 yrs , primary tumor </= 2.5 cm and node negative on preoperative clinical and imaging examination. Breast MRI was encouraged. Patient were treated with 6-12 Mev electrons using the IntraOp Mobetron device to a dose of 2100 cGy. A chest wall shield was used. Oncoplastic closure was used as indicated. Patients were scheduled for follow up at post op week 2, months 6,12,18 and then yearly until year five. Patients had mammograms yearly or as clinically indicated. There were 220 single fraction IOERT treatments delivered between 2012 and 2017. Sixteen patients were subsequently excluded from this analysis because they received subsequent whole breast radiation based on adverse pathology. Of the remaining 203 treatment, 6 patients had bilateral IOERT (total pts=197). The median follow up was 2.4 years. The median age was 65 yrs (range 40-91). Pathology was as follows: 23% pure DCIS, 71% IDC +/- DCIS, 5% ILC, 1% mixed. Twenty-four percent were stage 0, 72% were stage 1 and 5% stage 2. Eighty-nine percent were low-intermediate grade while 11% were high grade. Ninety percent were ER/PR positive. Eleven of 197 patients recurred (5.6%). Of those, 7 developed ipsilateral in-breast tumor recurrence (6 local recurrences and 1 new primary). IBTR= 3.6%. Two developed systemic recurrence and two developed a new contralateral primary. Median time to recurrence was 2.7 years. Our results show in-breast tumor recurrence rates for breast conservation with single fraction IOERT at 3.6%. These results are consistent with that of recently published randomized multicenter trials. Median follow-up for this review is 2.4 years and further follow-up is required.

Temporal Trends in the Use of Immediate Oncoplastic Techniques in Women Undergoing Breast Conserving Surgery and Adjuvant Radiation

Whole breast irradiation (WBI) is an integral component of breast conservation in the majority of women that undergo lumpectomy for breast cancer. Randomized trials also support the use of a lumpectomy cavity boost to further decrease the risk of in-breast tumor recurrence. Lumpectomy may be accompanied by oncoplastic techniques (OT) in which the breast tissue, sometimes including portions of the lumpectomy cavity , is rearranged in order to provide a more aesthetic appearance of the breast. OT may lead to challenges in identifying the lumpectomy cavity at the time of radiation planning. We set to determine the frequency of OT in our patients undergoing WBI. We hypothesized that the use of OT is increasing over time. We identified all women that underwent curative intent WBI (+/- regional nodal irradiation, RNI) in our department from 1/2013-6/2017. Women treated with partial breast irradiation and women without a primary tumor in the breast were excluded. We defined the modern cohort as women treated from 1/2015-present. The operative report(s) for each patient were individually reviewed to determine whether or not an OT was performed prior to initiation of WBI. Baseline patient and tumor characteristics were collected. The breast clinical target volume (CTV), lumpectomy gross tumor volume (GTV) and lumpectomy CTV were collected from the CT dataset. Our primary aim was to compare the rate of OT in the modern versus the earlier cohort using the chi-square test (p<0.05 considered significant). The Wilcoxon ranked sum test was used to compare differences in median lumpectomy GTV/CTV between the OT and non-OT groups. We identified 920 patients, 586 of which were in the modern cohort. The majority of patients had stage 0-II disease (N=877), a minority received neoadjuvant chemotherapy (N=82), and a minority underwent RNI (N=88). The median WBI dose was 50 Gy (IQR, 42.6-50 Gy) and 70% of patients underwent lumpectomy cavity boost (median dose=10 Gy, IQR=10-12 Gy). A total of 54 patients underwent OT: 37 reduction mammoplasties, 16 parenchymal advancement flaps, and 1 crescent mastopexy. The rate of OT was significantly higher in the modern vs. early cohort: 8.2% (48/586) vs. 1.8% (6/344), p<0.0001. Patients in the OT group vs. non-OT group had numerically larger median lumpectomy GTV [19.3 mL (IQR=12.0-32.6 mL) vs. 17.1 mL (IQR=10.1-28.0 mL), p=0.25] and median lumpectomy CTV [86.8 mL (IQR=52.4-135.5 mL) vs. 74.3 mL (IQR=48.8-112.8 mL), p=0.25]. In summary, we found an increasing rate in the use of OT in women undergoing lumpectomy for breast cancer at our institution. The majority of these women underwent lumpectomy cavity boost, which underscores the importance of radiation techniques that can more accurately target the lumpectomy cavity. These data support the prospective evaluation of an intraoperative radiation therapy boost in women that receive lumpectomy with immediate oncoplastic reconstruction as part of breast conservation.

Management of In-Breast Tumor Recurrence.

The management of isolated in-breast tumor recurrence is complex, requiring careful consideration of prior local therapies to plan future multimodality treatment. Options for surgical management have evolved from standard salvage mastectomy with axillary clearance and now include repeat breast conservation with axillary staging in select patients. Reattempting sentinel lymph node biopsy may avoid the morbidity of extensive axillary surgery and has been shown to be feasible in clinically node-negative patients with oncologically safe outcomes. In the adjuvant setting, partial breast irradiation has emerged as a valuable means to improve local control rates with limited associated toxicity and acceptable overall cosmesis. Furthermore, results from prospective trials are now available to support the use of chemotherapy in hormone-receptor negative subgroups, which is associated with improvements in long-term, disease-free, and overall survival.

Abstract P5-11-02: Predicting local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS)

Abstract Background: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of precursor, non-invasive breast lesions. Currently we lack accurate tools to stratify DCIS patients according to inherent risk of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC).Most DCIS patients are treated by breast-conversing surgery (BCS), followed by whole-breast radiotherapy (RT) for the majority of high-grade DCIS. The aim of this study was to identify novel biomarkers which predict recurrence after BCS +/- RT. Methods: A single institution study of 466 consecutive patients (median age 61, range 35-94) with DCIS treated by BCS between 2000 and 2010 was carried out. 271 patients with grade 3 DCIS received RT and 155 with grade 1/2 DCIS did not receive RT. For biomarker discovery, a case-control matched series of 200 patients (mean age = 61, range = 36-84) from the above audit that met the following criteria was selected: · 120 with low/intermediate-grade DCIS treated with BCS alone: 30 have recurred, 90 patients matched 3:1 have not recurred by 10 years. · 80 with high-grade DCIS treated by BCS plus RT: 20 have recurred, 60 patients matched 3:1 have not recurred by 10 years. Median follow-up was 7.4 years. RNA has been extracted and Affymetrix Clariom S whole-genome analysis has been performed and is currently being analysed. Results: In the cohort of 466 patients, 271 patients with high grade DCIS had BCS plus RT. Actuarial IBTR and IBC-IBTR in this group were 10% and 4% at 5 years and 18% and 6% at 10 years, respectively. 155 patients with low/intermediate grade DCIS had BCS alone. Actuarial overall IBTR and IBC-IBTR in this group were 6% and 2% at 5 years and 13% and 2% at 10 years respectively. In the high-grade, RT treated group, lesion size (P&amp;lt;0.001, P=0.003), presence of comedo necrosis (P=0.018, P=0.025) and the Van Nuys Prognostic Index (VNPI) (P=0.02, P=0.004) were significantly associated with overall IBTR and DCIS-IBTR. No factor was significantly associated with IBS-IBTR in the high grade group and no factor predicted for any IBTR in the low/intermediate group. Full genomic analysis of the 240 patient case-control matched cohort is underway and will be presented. Discussion: · This is the first DCIS biomarker discovery study using whole genome analysis and the matched cohort design looking separately at BCS + RT for high-grade DCIS and BCS only for low/intermediate grade DCIS. · Clinical parameters alone may have insufficient sensitivity to identify high-grade, RT-treated patients at risk of developing IBC-IBTR. · While recurrence rates in the low/intermediate grade DCIS group are lower than in the high-grade group, some patients do recur and there is a need to develop new tools which can identify low grade patients with a sufficiently high risk of recurrence to warrant additional treatment. Citation Format: Martinez-Perez C, Turnbull AK, Ekatah GE, Arthur LM, Fernando A, Sims AH, Thomas JS, Dixon JM. Predicting local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-11-02.

Abstract P4-06-03: Characteristics of CHEK2 mutation carriers in a large academic health center in Michigan

Abstract Background: Germline mutations in CHEK2, a cell-cycle checkpoint kinase, are associated with increased susceptibility to breast, colon, and other cancers. The clinical characteristics and cancer risks of patients with CHEK2 mutations is under investigation. Methods: Patients identified with a pathogenic germline CHEK2 mutation between September 2013 and April 2017 were evaluated. Clinical multigene panel testing using next generation sequencing technologies was utilized. All patients received comprehensive pre- and post-test genetic counseling. Genetic testing results, demographics, tumor characteristics and outcomes were analyzed. Results: A total of 107 CHEK2 mutation carriers were identified, of whom 88 (82%) were females. The vast majority were Caucasian (99%), and of those, 17 (16%) had Ashkenazi Jewish ancestry. The median age at time of genetic testing was 52 (range: 22-89). The most common mutations identified were: I157T (28%), c.1100delC (27%), p.S428F (15%) and c.1427C&amp;gt;T (9%). Seven of these patients (7%) were found to carry a second pathogenic cancer risk mutation: BRCA, ATM, NBN, NF1, and MUTYH. One patient was found to carry 3 pathogenic mutations (1100delC, ATM, and BRCA). Sixty-three (59%) patients had a prior diagnosis of malignancy, with a mean age of diagnosis of 53. Of the 88 females, the most common type of malignancy was breast cancer (55%), with a mean age of diagnosis of 52 (range: 35-79). Of the 19 males, breast cancer was seen in 4 patients. The most common known histopathology was invasive ductal carcinoma (72%), followed by DCIS (15%), invasive lobular carcinoma (9%), and papillary carcinoma (4%). Majority of the patients had breast tumors with low or moderate grade (62%), less than two centimeters (61%), node negative (70%), and estrogen/progesterone receptor positive/HER2neu negative (96%). Two patients had triple negative breast cancers. Of the 48 female mutation carriers with breast cancer, 38% underwent bilateral mastectomy. The 1- and 5-year survival was 100% with a median follow up of 57 months. Five of the 48 females developed a contralateral breast cancer, with a median time to contralateral recurrence of 6 years (range: 3-17). Two patients developed in-breast tumor recurrence at 9 and 19 years, respectively. Other cancers observed were papillary thyroid cancer (3 patients), melanoma (2 patients), and prostate (2 patients). One patient developed angiosarcoma of the chest wall two years after radiation therapy. Conclusion: Our study describes the unique clinical characteristics of CHEK2 mutation carriers in a US-based clinic at Beaumont Health. Majority of breast cancers were early stage, hormone receptor positive and demonstrated excellent outcomes. Despite the early stage, a significant proportion of patients underwent bilateral mastectomy. Additional pathogenic mutations were identified in 10% of patients; validating the importance of panel testing in assessing cancer risk. Future studies are needed to better define the clinical presentation, cancer risks, mutational spectrum, and outcomes of CHEK2 mutation carriers in order to provide tailored screening and management guidelines for this emerging population. Citation Format: Blankenship LM, Yadav S, Yumpo Cardenas P, Zakalik D. Characteristics of CHEK2 mutation carriers in a large academic health center in Michigan [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-03.

Breast conserving surgery in combination with intraoperative radiotherapy after previous external beam therapy: an option to avoid mastectomy.

Mastectomy is the standard procedure in patients with in-breast tumor recurrence (IBTR) or breast cancer after irradiation of the chest due to Hodgkin's disease. In certain cases a second breast conserving surgery (BCS) in combination with intraoperative radiotherapy (IORT) is possible. To date, data concerning BCS in combination with IORT in pre-irradiated patients are limited. This is the first pooled analysis of this special indication with a mature follow-up of 5years. Patients with IBTR after external beam radiotherapy (EBRT; treated in two centers) for breast cancer were included. Patients with previous EBRT including the breast tissue due to other diseases were also included. IORT was performed with the Intrabeam™-device using low kV X-rays. Clinical data including outcome for all patients and toxicity for a representative cohort (LENT-SOMA scales) were obtained. Statistical analyses were done including Kaplan-Meier estimates for local recurrence, distant metastasis and overall survival. A total of 41 patients were identified (39 patients with IBTR, 2 with Hodgkin`s disease in previous medical history). Median follow-up was 58months (range 4-170). No grade 3/4 acute toxicity occurred within 9weeks. Local recurrence-free survival rate was 89.9% and overall survival was 82.7% at 5years. Seven patients developed metastasis within the whole follow-up. BCS in combination with IORT in IBTR in pre-irradiated patients is a feasible method to avoid mastectomy with a low risk of side effects and an excellent local control and good overall survival.

Outcomes by molecular subtype after accelerated partial breast irradiation using single-entry catheters

PurposeTumor biology is being recognized as an important indicator of prognosis and risk of locoregional recurrence. Here, we determine actuarial recurrence rates by approximated molecular subtype for women treated with single-entry catheter accelerated partial breast irradiation (sAPBI). Methods and MaterialsOne thousand four hundred eighty-six women with invasive cancer having known ER, PR, and Her2 status and at least 1-year of followup were treated using MammoSite, Contura, or SAVI sAPBI from 2002 to 2014 at our institution. Actuarial recurrence rates were determined for the following four approximated molecular subtypes using the Kaplan–Meier method: luminal A (n = 1081), luminal B (n = 164), Her2 (n = 123), and triple-negative breast cancer (TNBC; n = 118). ResultsWith a median followup time of 3.3 years (range 1–13.6 years), the 5-year in-breast tumor recurrence rate was 2.6% overall, 2.1% for luminal A, 1.5% for luminal B, 4.9% for Her2, and 5.4% for TNBC. Luminal A and B subtypes, as compared with the more aggressive Her2 and TNBC subtypes combined, demonstrated lower 5-year in-breast tumor recurrence (2.1% vs. 5.1%, p = 0.021). The 5-year regional nodal recurrence rate was 1.4% overall, 1.4% for luminal A, 0% for luminal B, 1% for Her2, and 4.2% for TNBC. The 5-year locoregional control is 97.3% for luminal breast cancers and 93.8% for the more aggressive Her2 and TNBC subtypes collectively. ConclusionsLuminal cancers demonstrated excellent 5-year locoregional control with sAPBI. Although caution should be used when treating patients with the more aggressive Her2 and TNBC subtypes, these subtypes have demonstrated higher LRR with mastectomy and whole-breast irradiation. Further randomized comparisons are needed to determine the optimal treatment for these higher risk patients.

Impact of an In Situ Component on Outcome After In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy.

Among all in-breast tumor recurrences (IBTR) following breast-conserving therapy (BCT), some comprise metachronous new primaries (NPs) while others are true recurrences (TRs). Establishing this distinction remains a challenge. We studied 3932 women who underwent BCT for stage I-III breast cancer from 1998 to 2008. Of these, 115 (2.9%) had an IBTR. Excluding patients with inoperable/unresectable recurrences or simultaneous distant metastases, 81 patients with isolated IBTR comprised the study population. An IBTR was categorized as an NP rather than a TR if it included an in situ component. The log-rank test and Kaplan-Meier method were used to evaluate disease-free survival (DFS) and overall survival (OS), and univariate and multivariate analyses were performed using Cox proportional hazards regression models. At a median of 64.5months from IBTR diagnosis, 28 of 81 patients had DFS events. Five-year DFS was 43.1% in the TR group (p=0.0001) versus 80.3% in the NP group, while 5-year OS was 59.7% in the TR group versus 91.7% among those with NPs (p=0.0011). On univariate analysis, increasing tumor size, high grade, positive margins, lymphovascular invasion, node involvement, lack of axillary surgery, chemotherapy, radiation therapy, and IBTR type (TR vs. NP) were significantly associated with worse DFS. Controlling for tumor size and margin status, TRs remained significantly associated with lower DFS (hazard ratio 3.717, 95% confidence interval 1.607-8.595, p=0.002). The presence of an in situ component is associated with prognosis among patients with IBTR following BCT and may be useful in differentiating TRs and NPs.

Single Institution Analysis of In-Breast Tumor Recurrence Risk after No Radiation Versus Accelerated Partial Breast Irradiation for Ductal Carcinoma in Situ

Single Institution Analysis of In-Breast Tumor Recurrence Risk after No Radiation Versus Accelerated Partial Breast Irradiation for Ductal Carcinoma in Situ

Margin width and local recurrence after breast conserving surgery for ductal carcinoma in situ

IntroductionDuctal Carcinoma in situ (DCIS) represents 5% of symptomatic and 20–30% of screen detected cancers. Breast conserving surgery (BCS) ± radiotherapy is performed in over 70% of women with DCIS. What constitutes an adequate margin for BCS remains unclear. MethodsA single institution follow up study has been conducted of 466 patients with pure DCIS treated by BCS between 2000 and 2010 of whom 292 received whole breast radiotherapy and 167 did not. Patients were selected for radiotherapy based on perceived risk of in breast tumour recurrence (IBTR). Distance to nearest radial margin was measured; 10 patients had a margin width of <1 mm, 94 had widths of 1–2 mm and 362 had widths of >2 mm. There was no association of margin width and the use of radiotherapy. ResultsAt a median follow up of 7.2 years there were 44 IBTR (27 DCIS and 17 invasive). There was no evidence that margin widths >2 mm resulted in a lower rate of IBTR than margin widths of 1–2 mm. The actuarial IBTR rates at 5 and 10 years for margins of 1–2 mm were 9.0% (95% CI ± 5.9%) and 9.0% (95% CI ± 5.9%) respectively and for margins of >2 mm were 8.0% (95% CI ± 3.9%) and 13.0% (95% CI ± 3.9%) respectively. Odds Ratio for IBTR 1–2 mm vs >2 mm was 0.839 (95% CI 0.392–1.827) p = 0.846. In a multivariate analysis only DCIS size predicted for IBTR (HR 2.73 p < 0.0001). Conclusion1 mm appears a sufficient margin width for BCS in DCIS irrespective of whether patients receive radiotherapy.

Phase II study on radiofrequency ablation in stage 0 and I breast cancer without extensive intraductal components.

e12094 Background: We reported about a multi-center registration study on radiofrequency ablation (RFA) in early breast cancer (BC) (ASCO2012 #1119). Although various devices and ablation procedure were used, 5-year’s recurrence-free survival was 96% in 425 cases of T1BC treated with RFA alone. To validate complete pathological ablation in BC, we started a non-randomized phase II study in 2013 (UMIN000013836). Methods: Unilateral BC patients with stage 0 (TisN0M0) or I (T1N0M0 or T1N1miM0) were eligible. Tumor diameter of 2cm or less should be diagnosed by ultrasound and MR mammography. RFA was performed by Cool-tip RF ablation system (Covidien, USA). One month later, ablated tissue was collected by core needle biopsy or vacuum-assisted breast biopsy. Cell viability was determined by central review of independent pathologists using tumor specimens stained with hematoxylin–eosin and nicotinamide adenine dinucleotide (NADH) diaphorase. In case of complete ablation, breast irradiation and adjuvant therapy was planned. In case of incomplete ablation, partial mastectomy was recommended. The primary endpoint is complete ablation rate. The secondary endpoints are breast deformity after RFA, relapse-free survival and overall survival for 10 years. Two-step design consisting of 9 cases at 1st step and 20 cases at 2nd step was used for statistical evaluation. We expected complete ablation rate of 95% and 29 cases were needed to reject the null hypothesis that complete ablation rate would be less than 80% at lower threshold. Thus, 32 cases were required. Results: Thirty-six patients were enrolled between February 2013 and May 2016. The mean tumor size was 1.3 cm measured by MR mammography. Two patients were ineligible because of macrometastasis in a sentinel node. Of 34 eligible patients, one patient had viable cancer cells with NADH diaphorase staining in ablated specimens. Finally, complete ablation rate was 97%. As of January 2017, one patient, who refused adjuvant therapy and breast irradiation, had in-breast tumor recurrence adjacent to previously ablated lesion. Conclusions: Long-term follow-up should be needed, but RFA in early BC is a promising strategy instead of breast-conserving surgery. Clinical trial information: UMIN000013836.

Relationship of breast MRI to recurrence rates in patients undergoing breast-conservation treatment.

The effect of pre-operative MRI on the in-breast tumor recurrence rate (IBTR) of patients undergoing breast-conservation treatment (BCT) remains uncertain. We began to routinely perform pre-operative MRI in 2006. Our goal was to determine the effect of pre-operative MRI on IBTR. Retrospective review of a prospective database of all patients undergoing BCT (n=1396) from 2000 to 2010. IBTR were calculated using Kaplan-Meier estimates. 664 (47.6%) patients underwent pre-operative MRI. The use of MRI increased from 13.9% in 2000-2005 to 80.7% in 2006-2010. Ten percent of patients who underwent MRI were found to have an additional ipsilateral cancer, with a mean diameter of 1.6cm. The IBTR for patients with and without MRI were 4% vs. 8% at 8years (p=0.04). In multivariate analysis, radiation therapy and endocrine therapy were associated with decreased IBTR, but MRI was not (RR 0.77 (0.45-1.28)). For 1030 patients with invasive cancer, the IBTR at 8years with and without MRI was 4.2% vs. 7.3% (p=0.28). For 366 DCIS patients with and without MRI, the IBTR was 3.6% vs. 10.9% (p=0.06). In the subgroup of DCIS patients who did not receive radiation, the IBTR with and without MRI was 0% vs. 18.2% (p=0.08). Patients with an additional cancer found by MRI had a higher IBTR at 8years (10.1% vs. 3.3%, p=0.02). In a study analyzing BCT patients from one time period who rarely had a pre-operative MRI and a subsequent time period where most patients had MRI, the use of MRI was associated with a decrease in the IBTR on univariate, but not multivariate analysis. Patients who had additional cancers detected had a significantly higher IBTR.

Abstract P1-10-02: A signature predictive of early vs. late recurrence after radiation treatment (RT) for breast cancer that may inform the biology of early, aggressive recurrences

Abstract Purpose: Unmet clinical needs in breast cancer (BC) management include the identification of patients (pts) at high risk to fail locally despite standard local therapy including RT and understanding the biology of these recurrences. We previously reported1 a RT response signature and here extend those studies to identify a signature predictive of timing of recurrence after completion of RT (before or after 3 years). Methods: Two independent patient cohorts (treated with BCS) from non-randomized clinical trials were used for training and validation. The training cohort included 119 pts with in-breast tumor recurrence and the validation cohort had 25 pts with recurrences. Initial feature selection used Spearman's rank correlation correlating gene expression (14,806 genes) to recurrence time. Genes with sig. correlation (FDR &amp;lt;0.1) and large expression range (fold change &amp;gt;2) were used to train an elastic net penalized Poisson regression model. This model was locked and then applied to the validation dataset. Cox regression was used for both univariate and multivariable analyses (UVA and MVA). To identify biological-related concepts, Spearman's corr. coefficients of recurrence time to gene expression within the training cohort were used to generate a pre-ranked list upon which GSEA pathway analysis was performed. Results: Spearman's correlation identified 485 genes whose expression was significantly associated with recurrence time (early vs. late). Feature reduction further refined the gene list to 41 genes, which were retained within the signature and locked for further validation. In the training dataset the Spearman's correlation of the continuous score to recurrence time was 0.852 with a P-value of 1.3x10-34 and an AUC of 0.92. Application of this early vs late signature to an independent BC validation set accurately identifies pts with early vs. late recurrences (Spearman's corr.=0.537, p-value&amp;lt;0.007, AUC=0.74, sensitivity=0.71, specificity=0.73, PPV=0.77, NPV=0.67). In UVA and MVA the early vs. late recurrence signature remained the most significant factor associated with recurrence time. Although independent of intrinsic subtype, GSEA analysis of the 41 genes retained within the signature identifies proliferation and EGFR concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences is currently underway to assess phenotypic changes (proliferation and clonogenic survival as a measure of early and durable RT response) associated with the early and late recurrence-associated genes. Conclusion: In this study we derive a BC-specific RT signature predictive of early vs. late recurrence with biologic relevance and validate this signature for prediction of timing of recurrence in an independent clinical dataset. By identifying pts with tumors likely to recur sooner vs. later this signature has the potential to allow for a furthered understanding of the biology underlying early and late recurrences and has a potential to personalize RT, particularly in patients for whom treatment intensification is needed. 1. Clin Cancer Res. 2015 Aug 15;21(16):3667-77. Citation Format: Speers C, Chang L, Santola A, Liu M, Zhao SG, Chandler B, Olsen E, Bartelink H, Feng FY, Pierce LJ. A signature predictive of early vs. late recurrence after radiation treatment (RT) for breast cancer that may inform the biology of early, aggressive recurrences [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-02.

Locoregional recurrence by molecular subtype after multicatheter interstitial accelerated partial breast irradiation: Results from the Pooled Registry Of Multicatheter Interstitial Sites research group

PurposeTo determine in breast tumor recurrence (IBTR) and regional nodal recurrence (RNR) rates for women treated with multicatheter interstitial accelerated partial breast irradiation. Methods and MaterialsData from five institutions were collected for patients treated from 1992 to 2013. We report outcomes of 582 breast cancers with ≥1 year of followup. Molecular subtype approximation was performed using estrogen receptor, progesterone receptor, Her2, and grade. The Kaplan–Meier method was used to calculate overall survival, IBTR, RNR, and distant recurrence rates. Univariate and multivariate Cox proportional hazard models were performed to estimate risks of IBTR and RNR. ResultsWith a median followup time of 5.4 years, the 5-year IBTR rate was 4.7% overall, 3.5% for Luminal A, 4.1% for Luminal B, 5.2% for Luminal Her2, 13.3% for Her2, and 11.3% for triple-negative breast cancer. Positive surgical margins and high grade were associated with increased risk for IBTR, as was Her2 subtype in comparison with Luminal A subtype. Other individual subtypes comparisons did not show a significant difference. Analysis of Luminal A vs. all other subtypes demonstrated lower IBTR risk for Luminal A (5-year IBTR 3.5% vs. 7.3%, p = 0.02). The 5-year RNR rate was 2.1% overall, 0.3% for Luminal A, 4.6% for Luminal B, 2.6% for Luminal Her2, 34.5% for Her2, and 2.3% for triple-negative breast cancer. RNR risk was higher for women with Her2 compared to the other four subtypes and for Luminal B compared to Luminal A subtype. ConclusionsMolecular subtype influences IBTR and RNR rates in women treated with multicatheter interstitial accelerated partial breast irradiation.

Postoperative Radiotherapy After Breast-Conserving Surgery for Early-Stage Breast Cancer: A Review.

Radiotherapy (RT) after breast-conserving surgery for early-stage disease has become an integral part of breast cancer treatment. This article reviews the rationale and indications for adjuvant radiotherapy to the breast and regional lymph nodes. Randomized trials have demonstrated a significant benefit in tumor control in the treated breast following whole-breast RT that, in aggregate, has resulted in an overall survival advantage compared with breast-conserving surgery alone. Recent studies have further assessed the impact of regional nodal irradiation in women with either high-risk node-negative or node-positive disease and suggest a significant benefit in regional control and breast cancer recurrence, but not in overall survival. Toxic effects, including lymphedema, were increased in the cohorts receiving comprehensive nodal RT. The benefits from regional RT should be weighed against potential radiation-associated toxic effects. Randomized trials have also demonstrated equal efficacy and toxic effects between hypofractionated and conventionally fractionated RT in appropriately selected patients. In addition, current efforts incorporating clinical, pathologic, and molecular features are under way to identify patients for whom RT to the breast can be safely omitted. Adjuvant RT in early-stage breast cancer significantly reduces in-breast tumor recurrence and improves overall survival. Although risk reductions observed in randomized trials have been relatively consistent across series, the absolute benefit of RT is not equal for all women. Efforts are under way to identify which patients benefit the most from local or locoregional RT vs those at very low risk for recurrence in whom RT can be omitted. For patients who will benefit from RT and are appropriate candidates, hypofractionated RT should be strongly considered.

Assessing, Counseling, and Treating Patients at High Risk for Breast Cancer.

Identifying patients at high risk of carrying pathogenic variants in genes is a crucial part of providing both accurate counseling and evidence-based treatment recommendations. Current risk assessment models have strengths and weaknesses that may limit their applicability to specific clinical circumstances. Clinicians must have knowledge regarding variations in available models, how they should be used, and what data they can expect from specific models. In addition, indications for genetic testing are expanding, and the adoption of next-generation sequencing has allowed the creation of multigene testing panels. Complex consequences of panel testing have included an increase in the incidence of identifying variants of uncertain significance and the identification of pathogenic variants in genes for which treatment guidelines are not available. Women diagnosed with breast cancer who carry pathogenic variants in genes with proven associations with breast cancer (BRCA1/2) or highly likely associations (PTEN, PALB2) require additional risk assessment to facilitate treatment decisions that will limit in-breast tumor recurrence and contralateral breast cancer.

Comprehensive breast MRI: an update

With increasing use of clinical breast MRI and a plethora of novel techniques and sequences for lesion characterisation, a standardised approach to lesion description and reporting is increasingly important. This facilitates meaningful research and audit, particularly in the context of multicentre studies. To this end the American College of Radiology has recently published the 5th edition of the BI-RADS lexicon, with revision of the MRI section including addition of new descriptors, modification of others and deletion of some that were rarely helpful in practice, such as ‘stippled’ enhancement [1]. Categories for fibroglandular volume are now a to d, in line with the descriptors for mammography, thus avoiding confusion with assessment category. The degree of background parenchymal enhancement is now purely descriptive, from none/minimal to marked. A new descriptor is clustered rim enhancement (usually indicating DCIS). Non mass-like enhancement becomes non mass enhancement, whereas ‘ductal’ enhancement becomes linear. Overall the effect is of simplification and consistency with the mammography and ultrasound lexicons. The lexicon highlights the importance of a structured report, including the indication, scan technique, salient findings and critically, an overall assessment with a clear recommendation for further management. This approach has been validated in a number of studies correlating the assessment category with histopathological findings and/or long-term follow-up [2,3]. Use of a standardised lexicon, modified in the light of available evidence, has obviated some of the interpretative challenges of breast MRI. Use of supplemental diffusion weighted imaging may also be helpful [4]. Nonetheless, technical and clinical challenges remain. Artefacts are problematic, especially at 3T [5], and medical physics support is essential for good quality diagnostic scans, especially at higher field strength. Most importantly, it should be remembered that to date, despite the recognised superiority of breast MRI over any other modality for breast cancer detection and local staging, there is no hard evidence for improved patient outcomes. Two randomised controlled trials and seven comparative cohort studies have not shown any benefit for preoperative MRI in terms of re-excision rates; rather, there is a trend to higher mastectomy rates [6]. No convincing beneficial effects have been demonstrated in terms of in-breast tumour recurrence rates, disease-free survival or overall survival. Regarding assessment of response to neoadjuvant chemotherapy, MRI correlates better than mammography or ultrasound with final pathology, but false positive and negative studies are frequent, with underestimation of the amount of residual disease in up to 30% and overestimation in around 20% of cases [7,8]. Though evidence is accruing that MRI may be helpful in early response assessment, this is by no means standardised and is heavily dependent on many factors, not least tumour immunophenotype. Finally, though screening breast MRI for women at high risk has approximately double the sensitivity of mammography with encouraging stage shift and high rates of node negativity, there is as yet no evidence of a reduction in breast cancer mortality [9,10]. This workshop will provide an update on the BI-RADS lexicon and indications for breast MRI, with expert tuition in hands-on analysis of case studies.

Locoregional recurrence risk for women with various molecular subtypes of breast cancer treated with multicatheter interstitial accelerated partial-breast irradiation: Results from Pooled Registry of Multicatheter Interstitial Sites (PROMIS).

73 Background: This study was performed to determine in breast tumor recurrence (IBTR) and regional nodal recurrence (RNR) rates for women with different subtypes of invasive ductal breast cancer treated with multicatheter interstitial accelerated partial breast irradiation (mAPBI). Methods: Data from 5 institutions was collected for patients treated from 1992-2013. We report the outcomes of 821 women with 830 breast cancers, all with ≥ 1 year of follow-up after completion of mAPBI. Molecular subtype analysis was performed for 582 women in whom ER, PR, Her-2, and grade were known. The Kaplan-Meier method was used to calculate overall survival (OS), IBTR and RNR. A univariate proportional hazard model was performed to estimate the risk of IBTR based upon molecular subtype, age, grade, N-stage, T-stage, margin status, tumor size, dose rate, endocrine therapy, and chemotherapy. Results: The median age of our patient cohort was 60 years. 50.0% (n = 415) of women had luminal A, 6.9% (n = 57) luminal B, 5.7% (n = 47) luminal Her-2, 1.8% (n = 15) Her-2, and 5.8% (n = 48) triple negative breast cancer (TNBC); an additional 29.8% (n = 248) could not be subtyped. With a median follow-up time of 6.5 years, the 5-year OS of our patient cohort was 94.8%. The 5-year IBTR was 3.5% for luminal A, 4.1% for luminal B, 5.1% for luminal Her-2, 13.3% for Her-2, 11.3% for TNBC, and 1.7% for non-subtyped women. Positive surgical margins and high grade correlated with risk for IBTR; molecular subtype and other variables did not. The 5-year RNR rates were 0.3% for luminal A, 4.6% for luminal B, 2.6% for luminal Her-2, 34.5% for Her-2, and 2.3% for TNBC. RNR risk was significantly higher for women with Her-2 compared to the other 4 subtypes. In addition, risk of RNR was significantly higher for women with luminal B compared to those of luminal A. Conclusions: Women with Her-2 and luminal B breast cancer may have higher RNR but not IBTR risk after mAPBI, as compared with women with luminal A subtype. Further follow-up, correlation with use of trastuzumab, and comparison of outcomes with whole breast irradiation will be valuable.