Fertility Preservation in Young Women with Breast Cancer: Impact on Treatment and Outcomes.

BACKGROUND: The impact of chemotherapy timing on the fertility preservation (FP) decision is poorly understood. Here we evaluate factors associated with FP completion among women age ≤ 45 years with breast cancer who received chemotherapy and consulted with a reproductive endocrinology and infertility (REI) specialist, and report pregnancy and oncologic outcomes. PATIENTS AND METHODS: This retrospective review included all women age ≤ 45 years diagnosed with stage I-III unilateral breast cancer at Memorial Sloan Kettering Cancer Center between 2009 and 2015 who received chemotherapy and consulted with an REI specialist. Clinicopathologic features and factors associated with the decision to undergo FP were analyzed, and comparisons were made with the Wilcoxon rank-sum test, Chi-square test, or Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method. RESULTS: Among the 172 women identified, median age was 34 years (interquartile range 31-37 years). The majority of women were single (n = 99, 57.6%) and nulliparous (n = 134, 77.9%). Most women underwent FP (n = 121, 70.3%). Factors associated with the decision to undergo FP included younger median age (33 vs. 37 years, p < 0.001), having private insurance (p < 0.001), nulliparity (p < 0.001), and referral from Breast Surgery (p = 0.004). Tumor characteristics and treatments were similar between women who underwent FP and those who declined. Overall survival and recurrence-free survival were also similar between groups. Women who underwent FP were more likely to have a biological child after breast cancer treatment. CONCLUSIONS: Women underwent FP at high rates independent of timing of chemotherapy and oncologic factors. FP is associated with having a biological child and does not compromise oncologic outcomes.

Does Use of Neoadjuvant Chemotherapy Affect the Decision to Pursue Fertility Preservation Options in Young Women with Breast Cancer?

BACKGROUND: The American Society of Clinical Oncology guidelines recommend early referral to reproductive endocrinology and infertility (REI) specialists for young women diagnosed with breast cancer. Current practice patterns demonstrate an increased utilization of neoadjuvant chemotherapy (NAC). We evaluated premenopausal women with breast cancer after consultation with a Fertility Nurse Specialist (FNS) and determine factors associated with referral to REI specialists. METHODS: This retrospective review included all premenopausal women diagnosed at our institution with stage 0-III unilateral breast cancers between 2009 and 2015 who completed an FNS consultation. Clinicopathologic features and factors associated with referral to REI after FNS consultation were analyzed. RESULTS: A total of 334 women were identified. Median age was 35 years (interquartile range 32-38). The majority of women were single (n = 198, 59.3%) and nulliparous (n = 239, 71.6%). REI referrals were common (n = 237, 71.0%). The Breast Surgery service was the most frequent referring service (n = 194, 58.1%), with significantly more REI referrals compared to Breast Medicine and Genetics services (p = 0.002). Nulliparity was associated with REI referral (p < 0.0001). Adjuvant chemotherapy (p = 0.003) was associated with pursuing REI referral, whereas NAC (p < 0.001) was associated with declining REI referral. CONCLUSIONS: Most women elected to consult with an REI specialist, confirming strong interest in fertility preservation among premenopausal women with breast cancer. However, women receiving NAC more frequently declined referral to REI, suggesting that the need to start NAC may influence decisions regarding fertility preservation. With increasing utilization of NAC, our study supports the need for further counseling and education regarding fertility preservation for women undergoing NAC.

Increase in Utilization of Nipple-Sparing Mastectomy for Breast Cancer: Indications, Complications, and Oncologic Outcomes.

BACKGROUND: Nipple-sparing mastectomy (NSM) is increasingly performed for invasive breast cancer. Growing evidence supporting the oncologic safety of NSM has led to its widespread use and broadened indications. In this study, we examine the indications, complications, and long-term outcomes of therapeutic NSM. METHODS: From 2003 to 2016, women undergoing NSM for invasive cancer or ductal carcinoma in situ (DCIS) were identified from a prospectively maintained database. Patient and disease characteristics were compared by procedure year, while complications were compared by procedure year using generalized mixed-effects models accounting for a random surgeon effect. Overall survival and time to recurrence were examined. RESULTS: Of the 467 therapeutic NSMs, 337 (72%) were invasive cancer, 126 (27%) were DCIS, and 4 (1%) were phyllodes tumors. Median age was 45 years (range 24-75) and median follow-up among survivors was 39.4 months. Three hundred and fifty-seven (76.4%) cases were performed in 2011 or after. When comparing NSMs performed before and after 2011, there was a significant increase in NSMs performed for invasive tumors (58% vs. 77%; p < 0.001). There was no difference in family history, genetic mutations, smoking status, neoadjuvant chemotherapy, prior radiation, nodal involvement, or tumor subtype. Twenty-one (4.5%) nipple excisions were performed, of which 14 were performed for cancer at the nipple margin. Forty-four breasts (9.4%) had complications that required re-operation. Fifteen patients had locoregional recurrence or distant metastasis. CONCLUSIONS: NSM use for invasive carcinoma has doubled at our institution since 2011, while postoperative complications and recurrence rates remain low. Our experience supports the selective use of NSM in the malignant setting with careful patient selection.

Risk of Contralateral Breast Cancer in Women with Ductal Carcinoma In Situ Associated with Synchronous Ipsilateral Lobular Carcinoma In Situ.

BACKGROUND: Lobular carcinoma in situ (LCIS) is a risk factor for breast cancer, but the effect of LCIS found in association with ductal carcinoma in situ (DCIS) is unknown. In this study, we compared contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) rates among women with DCIS with or without synchronous ipsilateral LCIS treated with breast-conserving surgery (BCS). METHODS: DCIS patients undergoing BCS from 2000 to 2011 with a contralateral breast at risk were stratified by the presence or absence of synchronous ipsilateral LCIS with the index DCIS (DCIS + LCIS vs. DCIS). Those with contralateral, bilateral, or prior ipsilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated. RESULTS: Of 1888 patients identified, 1475 (78%) had DCIS and 413 (22%) had DCIS + LCIS. At median follow-up of 7.2 (range 0-17) years, 307 patients had a subsequent first breast event; 207 IBTR and 100 CBC. The 10-year cumulative incidence of IBTR was similar in both groups: 15.0% vs. 14.2% (log-rank, p = 0.8) for DCIS + LCIS vs. DCIS, respectively. The 10-year cumulative incidence of CBC was greater in the DCIS + LCIS group: 10.9% vs. 6.1% for DCIS (log-rank, p < 0.001). After adjustment for other factors, CBC risk remained higher in DCIS + LCIS compared with DCIS (hazard ratio 2.06, 95% confidence interval 1.36-3.11, p = 0.001); there was no significant difference in IBTR risk. CONCLUSIONS: Compared with DCIS alone, DCIS + LCIS is associated with similar IBTR risk but double the risk of CBC. This finding should inform treatment decisions, in particular regarding endocrine therapy for risk reduction.

Does Lymph Node Status Prior to Neoadjuvant Chemotherapy Influence the Number of Sentinel Nodes Removed?

BACKGROUND/OBJECTIVE: Recent prospective trials support the use of sentinel lymph node biopsy (SLNB) in breast cancer patients after neoadjuvant chemotherapy (NAC) with a lower false-negative rate if three or more sentinel lymph nodes (SLNs) are identified. In this study, we investigated whether the pre-NAC axillary lymph node status influences the number of SLNs identified. METHODS: Stage I-III breast cancer patients who received NAC and underwent SLNB from May 2014 to April 2016 were identified from an institutional prospective database. Clinical and pathological factors among clinically node-negative (cN-) and clinically node-positive (cN+) patients who converted to cN- post-NAC were compared. Generalized linear mixed models analyzed factors associated with the number of SLNs removed. RESULTS: Among 343 patients who underwent SLNB during the study period, 335 (98%) had at least one SLN identified, and subsequently comprised the study population. The median number of SLNs identified was 4 (range 1-14), which did not differ according to pre-NAC nodal status (P = 0.15). Overall, 85% of patients had three or more SLNs identified (80% cN- group vs. 89% cN+ group; P = 0.02). On univariable analysis, age < 50 years and presenting with a positive axillary node were significantly associated with identifying three or more SLNs. CONCLUSIONS: Our study confirms that SLNB was successfully performed in 98% of our patients after NAC, with very few failed mapping procedures. In the post-NAC setting, the median number of SLNs identified was four, and the status of the axilla prior to NAC did not negatively affect the number of SLNs identified.

Most Breast Cancer Patients with T1-2 Tumors and One to Three Positive Lymph Nodes Do Not Need Postmastectomy Radiotherapy.

BACKGROUND/OBJECTIVE: Guidelines concur that postmastectomy radiation therapy (PMRT) in T1-2 tumors with one to three positive (+) lymph nodes (LNs) decreases locoregional recurrence (LRR) but advise limiting PMRT to patients at highest risk to balance against potential harms. In this study, we identify the risks of LRR after mastectomy in patients with T1-2N1 disease, treated with modern chemotherapy, and identify predictors of LRR when omitting PMRT. METHODS: Patients with T1-2N1 breast cancer undergoing mastectomy between 1995 and 2006 were categorized by receipt of PMRT. The Chi square test compared the clinicopathologic features between both groups, and Kaplan-Meier and Cox regression analysis was used to determine the rates of LRR, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Overall, 1087 patients (924 no PMRT, 163 PMRT) were included in the study, with a median follow-up of 10.8 years (range 0-21). We identified 63 LRRs (56 no PMRT, 7 PMRT), and 10-year rates of LRR with and without PMRT were 4.0% and 7.0%, respectively. Patients receiving PMRT were younger (p = 0.019), had larger tumors (p = 0.0013), higher histologic grade (p = 0.029), more positive LNs (p < 0.0001), lymphovascular invasion (LVI) (p < 0.0001), extracapsular nodal extension (p < 0.0001), and macroscopic LN metastases (p < 0.0001). There was no difference in LRR, RFS, or OS between groups. On multivariate analysis, age < 40 years (p < 0.0001) and LVI (p < 0.0001) were associated with LRR in those not receiving PMRT. CONCLUSION: Consistent with the guidelines, 85% of patients with T1-2N1 were spared PMRT at our center, while maintaining low LRR. Age < 40 years and the presence of LVI are significantly associated with LRR in those not receiving PMRT.

Outcomes for Women with Minimal-Volume Ductal Carcinoma In Situ Completely Excised at Core Biopsy.

BACKGROUND: Overdiagnosis and overtreatment of ductal carcinoma in situ (DCIS) are concerns, especially for women with low-volume, screen-detected DCIS. This study aimed to evaluate the outcomes for such patients. METHODS: Women who had minimal-volume DCIS (mDCIS, defined as DCIS diagnosed by core biopsy but with no residual disease on the surgical excision) treated with breast-conserving surgery from 1990 to 2011 were identified. Ipsilateral and contralateral breast events (IBE and CBE) were compared by competing-risk (CR) analysis. Kaplan-Meier (KM) estimates and log-rank tests were used to evaluate covariates. RESULTS: The study identified 290 cases of mDCIS. The median age of the patients was 53 years. Radiation therapy (RT) was performed for 27.6% and endocrine therapy for 16.2% of the patients. The median follow-up period was 6.8 years. Overall, the IBE rates were 4.3% at 5 years and 12.3% at 10 years. Among the women not receiving RT, the 5- and 10-year IBE rates (5.4 and 14.5%) were higher than the CBE rates (1.8 and 2.7%). Among those receiving RT, the IBE rates (1.5 and 6.0%) were lower than the CBE rates (4.1 and 15.6%). The women receiving RT trended toward significantly lower IBE rates (p = 0.07). Age, grade, and endocrine therapy were not significantly associated with IBE risk. CONCLUSIONS: Among the patients with mDCIS who did not receive RT, the IBE risk was substantially higher than the CBE risk, demonstrating that even DCIS of very low volume is associated with clinically relevant disease. The finding that the IBE risk was greater than the CBE risk supports current strategies that treat DCIS as a precursor rather than a risk marker. Women with mDCIS are not at negligible risk for IBE in the absence of adjuvant therapy.

Contralateral Breast Cancer Risk in Women with Ductal Carcinoma In Situ: Is it High Enough to Justify Bilateral Mastectomy?

BACKGROUND: Women with ductal carcinoma in situ (DCIS) are increasingly choosing bilateral mastectomy. We sought to quantify rates of contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) for DCIS, and to compare risk factors for CBC and IBTR. METHODS: From 1978 to 2011, DCIS patients undergoing BCS with a contralateral breast at risk were identified from a prospectively maintained database. The association of clinicopathologic and treatment factors with CBC and IBTR were evaluated using Kaplan-Meier analysis, multivariable Cox regression, and competing risk regression (CRR). RESULTS: Of 2759 patients identified, 151 developed CBC and 344 developed IBTR. Five- and 10-year Kaplan-Meier CBC rates were 3.2 and 6.4%. Overall, 10-year IBTR rates were 2.5-fold higher than CBC rates, and, without radiation, 4-fold higher. On CRR, 5- and 10-year rates were 2.9 and 5.8% for CBC, and 7.8 and 14.5% for IBTR. CBC risk and invasive CBC risk were not significantly associated with age, family history, presentation, nuclear grade, year of surgery, or radiation. By multivariable Cox regression, endocrine therapy was associated with lower CBC risk (hazard ratio 0.57, p = 0.03). Ten-year risk of subsequent CBC in the subset of patients who developed IBTR was similar to the cohort as a whole (8.1 vs. 6.4%). CONCLUSIONS: CBC rates were low across all groups, including those who experienced IBTR. CBC was not associated with factors that increase IBTR risk. While factors associated with IBTR risk are important in decision making regarding management of the index DCIS, they are not an indication for contralateral prophylactic mastectomy.

Pleomorphic lobular carcinoma in situ of the breast: a single institution experience with clinical follow-up and centralized pathology review.

PURPOSE: The natural history of pleomorphic lobular carcinoma in situ (PLCIS) remains largely unknown. METHODS: A pathology database search (1995-2012) was performed to identify patients diagnosed with an LCIS variant. Patients with synchronous breast cancer and/or no evidence of pleomorphism were excluded. Original slides were re-evaluated by three pathologists to identify a consensus cohort of PLCIS. Borderline lesions with focal atypia were classified as LCIS with pleomorphic features (LCIS-PF). Clinical data were obtained from medical records. RESULTS: From 233 patients, we identified 32 with an LCIS variant diagnosis and no concurrent breast cancer. Following review, 16 cases were excluded due to lack of pleomorphism. The remaining 16 were classified as PLCIS (n = 11) and LCIS-PF (n = 5). 12/16 patients were treated with surgical excision ± chemoprevention. Patients with a prior breast cancer history and those having mastectomy were excluded from outcome analysis. Among the remaining 7 patients with PLCIS/LCIS-PF, 4/7 (57%) developed ipsilateral breast cancer at a median follow-up of 67 months. Median age at the time of breast cancer diagnosis was 56 years old and median time from PLCIS/LCIS-PF to cancer diagnosis was 59 months (range 45-66 months). The four cancers included 1 invasive lobular carcinoma (ILC), 1 microinvasive ILC, 1 invasive ductal carcinoma, and 1 ductal carcinoma in situ. CONCLUSIONS: We confirm that PLCIS in isolation is indeed a rare entity, further contributing to the difficulty in determining the actual risk conferred by this lesion. Long-term follow-up data on larger cohorts are needed to define standardized management and outcomes for patients with PLCIS.

Lobular Carcinoma in Situ: A 29-Year Longitudinal Experience Evaluating Clinicopathologic Features and Breast Cancer Risk.

PURPOSE: The increased breast cancer risk conferred by a diagnosis of lobular carcinoma in situ (LCIS) is poorly understood. Here, we review our 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk. PATIENTS AND METHODS: Patients participating in surveillance after an LCIS diagnosis are observed in a prospectively maintained database. Comparisons were made among women choosing surveillance, with or without chemoprevention, and those undergoing bilateral prophylactic mastectomies between 1980 and 2009. RESULTS: One thousand sixty patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27 to 83 years). Fifty-six patients (5%) underwent bilateral prophylactic mastectomy; 1,004 chose surveillance with (n = 173) or without (n = 831) chemoprevention. At a median follow-up of 81 months (range, 6 to 368 months), 150 patients developed 168 breast cancers (63% ipsilateral, 25% contralateral, 12% bilateral), with no dominant histology (ductal carcinoma in situ, 35%; infiltrating ductal carcinoma, 29%; infiltrating lobular carcinoma, 27%; other, 9%). Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% with chemoprevention; 21% with no chemoprevention; P < .001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P = .008). CONCLUSION: We observed a 2% annual incidence of breast cancer among women with LCIS. Common clinical factors used for risk prediction, including age and family history, were not associated with breast cancer risk. The lower breast cancer incidence in women opting for chemoprevention highlights the potential for risk reduction in this population.

Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion.

PURPOSE: Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC. METHODS: Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.0 microarrays. RESULTS: Unsupervised hierarchical clustering of 40 LCIS samples identified 2 clusters of LCIS distinguished by 6431 probe sets (p < 0.001). Genes identifying the clusters included proliferation genes and other genes related to cancer canonical pathways such as TGF beta signaling, p53 signaling, actin cytoskeleton, apoptosis and Wnt-Signaling pathway. A supervised analysis to identify differentially expressed genes (p < 0.001) between normal epithelium, LCIS, and ILC, using 23 patient-matched triplets of N, LCIS, and ILC, identified 169 candidate precursor genes, which likely play a role in LCIS progression, including PIK3R1, GOLM1, and GPR137B. These potential precursor genes map significantly more frequently to 1q and 16q, regions frequently targeted by gene copy number alterations in LCIS and ILC. CONCLUSION: Here we demonstrate that classic LCIS is a heterogeneous disease at the transcriptomic level and identify potential precursor genes in lobular carcinogenesis. Understanding the molecular heterogeneity of LCIS and the potential role of these potential precursor genes may help personalize the therapy of patients with LCIS.

Is there a role for routine screening MRI in women with LCIS?

Women with lobular carcinoma in situ (LCIS) have an elevated breast cancer risk, yet the benefit of MRI screening is unclear. We examined cancer detection rates with mammography alone versus mammography plus MRI in this high-risk population. From a prospectively maintained, single-institution database, we identified 776 patients diagnosed with LCIS after the adoption of screening MRI in April 1999. In addition to annual mammography and breast exam, MRI was used at the discretion of the physician and patient. Kaplan-Meier methods and landmark analyses at 1, 2, and 3 years following LCIS diagnosis were performed to compare rates of cancer detection with or without MRI. MRI screening was performed in 455 (59 %) patients (median, 3/patient). Median time from LCIS diagnosis to first MRI was 9 months (range 0.3-137 months). Patients undergoing MRI were younger (p < 0.0001), premenopausal (p < 0.0001), and more likely to have ≥1 first-degree relative with breast cancer (p = 0.009). At a median follow-up of 58 months, 98/776 (13 %) patients developed cancer. The crude cancer detection rate in both screening groups was 13 %. MRI was not associated with earlier stage, smaller size, or node negativity. Landmark analyses at 1, 2, and 3 years after LCIS diagnosis failed to demonstrate increased cancer detection rates among women having MRI (p = 0.23, 0.26, and 0.13, respectively). Although a diagnosis of LCIS remains a significant risk factor for breast cancer, the routine use of MRI does not result in increased cancer detection rates (short-term), nor does it result in earlier stage at diagnosis, illustrating the importance of defining optimal screening strategies for high-risk patients based on tumor biology rather than numerical risk.

Superior mesenteric arteriovenous fistula embolisation complicated by bowel ischaemia.

Superior mesenteric arteriovenous fistulas are rare, especially when iatrogenic in origin. Management of these fistulas can be surgical or endovascular. Endovascular embolisation is the preferred modality with a low rate of complications. Among the reported complications, bowel ischaemia is considered an unlikely occurrence. We report a case of a complex iatrogenic arterioportal fistula that was managed by endovascular embolisation and controlled through both its inflow and outflow, and was later complicated by bowel ischaemia.

Is there a low-grade precursor pathway in breast cancer?

BACKGROUND: Newly proposed models of breast tumorigenesis suggest that low- and high-grade lesions have distinct tumor progression pathways. Our objective was to examine the relationship between histologic grade and molecular subtype in women with lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) who developed subsequent ipsilateral invasive breast cancers. METHODS: Patients who underwent surveillance for classical LCIS (1994-2007) and those followed after lumpectomy±radiation for DCIS (1991-2004) who developed subsequent ipsilateral invasive cancers and had available tissue blocks were included. ER/PR/HER2 surrogates were used for molecular subtype. RESULTS: Material was available for 27 patients with classical LCIS who developed ipsilateral invasive cancer (12 invasive ductal cancer [IDC], 14 invasive lobular, 1 mixed), and 26 patients with DCIS (12 low-grade [LG], 14 high-grade [HG]) who developed ipsilateral IDC. No difference in age at diagnosis or median time to invasive cancer existed between groups with LCIS and DCIS. When stratified by grade, 0 of 12 LG-DCIS developed LG-IDC (3 grade II; 9 grade III), and only 1 of 12 LCIS patients who developed IDC had LG-IDC. Thirteen (93%) patients with HG-DCIS developed HG-IDC. In contrast, molecular subtype was maintained in 23 of 27 (85%) cases of LCIS and in 18 of 26 (69%) cases of DCIS. CONCLUSIONS: These data do not support a low-grade precursor pathway characterized by LCIS and LG-DCIS. ER/PR and HER2 status have a high rate of concordance between in situ and subsequent invasive lesions. Additional studies of metachronous in situ and invasive lesions are needed to better understand pathways of breast tumorigenesis.