Meena S. Moran

Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer

PURPOSE Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer. METHODS A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus. RESULTS Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. CONCLUSION The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. J Clin Oncol 32. 2014 American Society of Clinical Oncology®, American Society for Radiation Oncology®, and Society of Surgical Oncology®. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology.

Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer.

PurposeControversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer.MethodsA multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.ResultsPositive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.ConclusionThe use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.

Local‐Regional Breast Cancer Recurrence: Prognostic Groups Based on Patterns of Failure

The purpose of this study was to determine the outcome of breast cancer patients sustaining local‐regional failure as their first site of relapse in an effort to group patients into prognostic categories. Between January 1970 and December 1992, over 4,000 patients with breast cancer were treated at our facilities with mastectomy or conservative surgery with radiation therapy (CS + RT). Two hundred thirteen patients sustained local‐regional relapse without evidence of distant metastasis as their first site of failure, and they served as the population base for this study. The 213 patients with local‐regional recurrence of disease were distributed as follows: 68 patients relapsed in the ipsilateral breast following CS + RT within 5 years of original diagnosis (EARLYBR). Fifty‐one patients relapsed in the ipsilateral breast after 5 years from original diagnosis (LATEBR). Thirty‐five patients relapsed in the chest wall within 5 years following mastectomy (EARLCW). Eighteen patients relapsed in the chest wall later than 5 years following mastectomy, and 41 patients failed in the regional lymphatics following mastectomy or CS + RT (REGREC). Patients with breast relapses were generally treated with salvage mastectomy, and patients with chest wall or regional nodal relapses were treated with radiation to the chest wall, regional nodes, or both. Systemic therapy at the time of local‐regional relapse was highly individualized, ranging from observation to tamoxifen to high‐dose chemotherapy with transplantation. With a median follow‐up of 14 years, the overall 10‐year survival for all 213 patients was 61%, and the 10‐year distant metastasis‐free rate was 59%. Patients with a LATEBR had a relatively favorable prognosis with a 5‐year postrelapse distant metastasis rate of 80%. Patients with EARLYBR and LATECW had a similar prognosis, with a 5‐year postrelapse distant metastasis rate of 61% and 65%, respectively. Patients with an EARLCW had a 5‐year distant recurrence‐free rate following a local relapse of 42%. Ten‐year survivals from original diagnosis were 62% and 50%, respectively, and distant metastasis‐free survival rates were 56% and 52%, respectively. Patients suffering REGREC following mastectomy or CS + RT carried a poor prognosis with a 10‐year survival of 33% and a 10‐year distant metastasis‐free rate of 30%. Patients sustaining local‐regional relapse as a first site of failure may be divided into prognostic groups. Patients with LATEBR have a relatively favorable prognosis. Patients with EARLYBR and CWREC have a poorer prognosis with a distant metastatic rate of approximately 50% within 5 years of local‐regional relapse. Patients with REGREC have the poorest prognosis. Placing patients with breast cancer and local‐regional relapse into these prognostic categories may be helpful in decision making regarding the role of systemic therapy at the time of local‐regional relapse.

Society of Surgical Oncology–American Society for Radiation Oncology–American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma In Situ

Background Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation (WBRT). Methods A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7883 patients and other published literature as the evidence base for consensus. Results Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2 mm margins. Negative margins less than 2 mm alone are not an indication for mastectomy, and factors known to impact rates of IBTR should be considered in determining the need for re-excision. Conclusion The use of a 2 mm margin as the standard for an adequate margin in DCIS treated with WBRT is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcome, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm.

Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition

The epithelial–mesenchymal transition (EMT) is a process in which polarized epithelial cells are converted into motile mesenchymal cells. During cancer development, EMT is conducive to tumor dissemination and metastatic spread. While overexpression of metadherin (MTDH) in breast cancer cell lines and tissues has been found to be associated with aggressive tumor behavior, its precise role in invasion and metastasis is largely unknown. Here we report that MTDH overexpression could significantly enhance the invasion and migration of breast cancer cells by inducing EMT. Metadherin overexpression led to upregulation of mesenchymal marker fibronectin, downregulation of epithelial marker E‐cadherin, and the nuclear accumulation of beta‐catenin. Also, transcription factors Snail and Slug were upregulated in breast cancer cells overexpressing MTDH. Overexpression of MTDH enhanced the invasiveness and migration ability of breast cancer cells in vitro. In addition, overexpression of MTDH led to increased acquisition of CD44+/CD24−/low markers that are characteristic of breast cancer stem cells. We also showed that NF‐kappa was involved in the expression of EMT‐related markers. Taken together, our results suggest that MTDH could promote EMT in breast cancer cells in driving the progression of their aggressive behavior. (Cancer Sci 2011; 102: 1151–1157)

Ductal carcinoma in situ treated with breast-conserving surgery and radiotherapy: A comparison with ECOG study 5194†

Recent data from Eastern Cooperative Oncology Group (ECOG) Study 5194 (E5194) prospectively defined a low‐risk subset of ductal carcinoma in situ (DCIS) patients where radiation therapy was omitted after lumpectomy alone. The purpose of the study was to determine the ipsilateral breast tumor recurrence (IBTR) in DCIS patients who met the criteria of E5194 treated with lumpectomy and adjuvant whole breast radiation therapy (RT).

Ductal Carcinoma In Situ With Microinvasion: Prognostic Implications, Long-Term Outcomes, and Role of Axillary Evaluation

PURPOSE To compare the clinical-pathologic features and long-term outcomes for women with ductal carcinoma in situ (DCIS) vs. DCIS with microinvasion (DCISM) treated with breast conservation therapy (BCT), to assess the impact of microinvasion. PATIENTS AND METHODS A total of 393 patients with DCIS/DCISM from our database were analyzed to assess differences in clinical-pathologic features and outcomes for the two cohorts. RESULTS The median follow-up was 8.94 years, and the mean age was 55.8 years for the entire group. The DCISM cohort was comprised of 72 of 393 patients (18.3%). Surgical evaluation of the axilla was performed in 58.3% (n = 42) of DCISM vs. 18.1% (n = 58) of DCIS, with only 1 of 42 DCISM (2.3%) vs. 0 of 58 DCIS with axillary metastasis. Surgical axillary evaluation was not an independent predictor of local-regional relapse (LRR), distant relapse-free survival (DRFS), or overall survival (OS) in Cox proportional hazards analysis (p > 0.05). For the DCIS vs. DCISM groups, respectively, the 10-year breast relapse-free survival was 89.0% vs. 90.7% (p = 0.36), DRFS was 98.5% vs. 97.9% (p = 0.78), and OS was 93.2% vs. 95.7% (p = 0.95). The presence of microinvasion did not correlate with LRR, age, presentation, race, family history, margin status, and use of adjuvant hormonal therapy (all p > 0.05). In univariate analysis, pathology (DCIS vs. DCISM) was not an independent predictor of LRR (hazard ratio [HR], 1.58; 95% confidence interval [CI], 0.58-4.30; p = 0.36), DRFS (HR, 0.72; 95% CI, 0.07-6.95; p = 0.77), or OS (HR, 1.03; 95% CI, 0.28-3.82; p = 0.95). CONCLUSIONS Our data imply that the natural history of DCISM closely resembles that of DCIS, with a low incidence of local-regional and distant failures. On the basis of our large dataset, the incidence of axillary metastasis in DCISM appears to be small and not appear to correlate to outcomes, and thus, microinvasion alone should not be the sole criterion for more aggressive treatment.

Long-term outcomes and clinicopathologic differences of African-American versus white patients treated with breast conservation therapy for early-stage breast cancer.

African–American (AA) and white patients with early–stage disease who were treated with breast conservation therapy (BCT) were examined to detect differences in clinicopathologic features and outcomes as a function of race.

Effects of breast-conserving therapy on lactation after pregnancy

BACKGROUNDAs the incidence of breast-conserving therapy in women of childbearing years increases, patient concerns regarding subsequent pregnancies and lactation have become more prevalent. There is a paucity of data regarding lactation outcomes in women who have undergone breast-conserving therapy and then sustained full-term pregnancies. Our objective was to evaluate lactation outcomes in patients with early-stage breast cancer treated with breast-conserving therapy. METHODSWe reviewed a database of over 3,000 patients treated from 1965 to 2003 to identify our cohort of premenopausal women who underwent breast-conserving therapy and subsequently sustained full-term pregnancies. Lactation outcome parameters (breast swelling, ability to lactate, and volume of lactation in the treated and untreated breasts) were the main outcome measures. RESULTSWe identified 28 pregnancies in 21 patients. The median age at diagnosis was 32 years. One patient underwent bilateral breast treatment; therefore, a total of 22 breasts were irradiated. All patients interviewed reported little or no swelling of the treated breast during pregnancy. Of the patients studied, 4 (18.2%) elected pharmacological suppression of lactation. Of the remaining 18 breasts, lactation occurred in 10 (55.6%), did not occur in 7 (38.9%) and was unknown for 1 (5.5%). The volume was reported as significantly diminished in 80% of breasts treated. Lactation in the contralateral breast occurred in all patients who did not undergo pharmacological suppression. CONCLUSIONPatients can experience successful lactation in the contralateral, untreated breast after breast-conserving therapy. In the treated breast, functional lactation is possible but is significantly diminished in the majority of patients.

Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups

BACKGROUND Despite significant differences in age of onset and incidence of breast cancer between Caucasian (CA), African-American (AA) and Korean (KO) women, little is known about differences in BRCA1/2 mutations in these populations. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations and the association between BRCA1/2 mutation status and secondary malignancies among young women with breast cancer in these three racially diverse groups. METHODS Patients presenting to our breast cancer follow-up clinics selected solely on having a known breast cancer diagnosis at a young age (YBC defined as age <45 years at diagnosis) were invited to participate in this study. A total of 333 eligible women, 166 CA, 66 AA and 101 KO underwent complete sequencing of BRCA1/2 genes. Family history (FH) was classified as negative, moderate or strong. BRCA1/2 status was classified as wild type (WT), variant of uncertain significance (VUS) or deleterious (DEL). RESULTS DEL across these three racially diverse populations of YBC were nearly identical: CA 17%, AA 14% and KO 14%. The type of DEL differed with AA having more frequent mutations in BRCA2, compared with CA and KO. VUS were predominantly in BRCA2 and AA had markedly higher frequency of VUS (38%) compared with CA (10%) and KO (12%). At 10-year follow-up from the time of initial diagnosis of breast cancer, the risk of secondary malignancies was similar among WT (14%) and VUS (16%), but markedly higher among DEL (39%). CONCLUSIONS In these YBC, the frequency of DEL in BRCA1/2 is remarkably similar among the racially diverse groups at 14%-17%. VUS is more common in AA, but aligns closely with WT in risk of second cancers, age of onset and FH.