Survival Outcomes in Women with Unilateral, Triple-Negative, Breast Cancer Correlated with Contralateral Prophylactic Mastectomy.

BACKGROUND: Despite increased utilization of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in average-risk women with unilateral breast cancer. CPM may be of heightened interest to patients with triple negative breast cancer (TNBC) because these patients are more likely to have BRCA1 mutation-associated disease and are not candidates for the chemoprevention benefits of adjuvant endocrine therapy. METHODS: Survival and recurrence outcomes were evaluated for all TNBC patients from a multi-institutional database (1999-2018) at two academic cancer programs in two metropolitan cities of the Northeast and Midwest. Median follow-up time was 3.7 years. RESULTS: Seven hundred and nighty six TNBC patients were evaluated and 15.45% underwent CPM. Women undergoing CPM were more likely to be white (p < 0.001), younger (p < 0.001), and underwent genetic testing (p < 0.001). A borderline survival benefit was observed for TNBC patients undergoing CPM (5-year overall survival 95.1% vs. 85.0%; p = 0.05). There was no difference in survival when BRCA mutation carriers were excluded (5-year overall survival 94.1% vs. 85.2%; p = 0.12). For BRCA mutation carriers, a numeric trend was observed for improved survival for patients undergoing CPM (5-year overall survival 97.2% vs. 84.1%; p = 0.35). Among patients not undergoing CPM, the rate of developing a new primary breast cancer was 2.2% (15/673). Among these 15 patients, 20% (3/15) were known BRCA mutation carriers. CONCLUSIONS: Our data demonstrate no survival benefit for TNBC patients without BRCA1/2 mutations undergoing CPM.

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer.

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Radial Scars and Complex Sclerosing Lesions of the Breast: Prevalence of Malignancy and Natural History Under Active Surveillance.

BACKGROUND: When needle core biopsies (NCBs) of the breast reveal radial scar or complex sclerosing lesions (RSLs), excision is often recommended despite a low risk of malignancy in the modern era. The optimal management of NCBs revealing RSLs is controversial, and understanding of the natural history of unresected RSLs is limited. METHODS: We retrospectively analyzed pathology and imaging data from 148 patients with NCB revealing RSL without atypia from 2015 to 2019 to determine the prevalence of malignancy and the behavior of RSLs undergoing active surveillance (AS). RESULTS: The mean age of patients was 52 years, and most lesions were screen-detected (91%). The median lesion size was 6.0 mm (range 2-39). Most patients (66%, n = 98) underwent immediate surgery, while 34% (n = 50) of patients underwent AS, with a median follow-up of 16 months (range 6-51). Of the excised RSLs, 99% (n = 97) were benign and 1% (n = 1) revealed ductal carcinoma in situ (DCIS). In 17% (n = 17) of cases, additional high-risk lesions were discovered upon excision. Among the 50 patients undergoing AS, no lesions progressed on interval imaging. CONCLUSIONS: In this cohort, 99% of RSLs undergoing excision were benign, 1% revealed DCIS, and there were no invasive cancers. In the first study of patients with RSLs undergoing AS, we found that all lesions either remained stable or resolved. We propose that the vast majority of patients with RSL on NCB can be safely offered AS, and that routine excision is a low-value intervention.

Characterization of Recurrences Following Second Breast-Conserving Surgery with Intraoperative Radiotherapy.

BACKGROUND: Breast-conserving surgery with breast re-irradiation is an emerging technique in the treatment of selected cases of locally recurrent breast cancer. Further information is needed to characterize factors that may select for an appropriate patient population for this treatment approach. METHODS: We report herein a single-institution retrospective analysis of patients with ipsilateral breast cancer recurrence treated with a second breast-conserving therapy with intraoperative radiotherapy. Patient records were reviewed to analyze toxicity, further recurrence, and characteristics of recurrent patients following this treatment approach. RESULTS: We included 57 patients in the analysis. At median follow-up of 24.5 months, ipsilateral breast tumor recurrence occurred in six patients (11%), four of which localized to the quadrant of the initial recurrent disease and two of which recurred elsewhere in the treated breast. Locoregional control was 89%, and disease-free survival was 81%. Only one patient was found to have grade 3 or greater toxicity. CONCLUSION: A second breast-conserving surgery with intraoperative radiotherapy is tolerable with acceptable toxicity for patients with locally recurrent disease refusing mastectomy. Prospective clinical trials are needed to define the subset of patients who may be appropriate for this treatment approach as an alternative to mastectomy.

Prediction of blood-based biomarkers and subsequent design of bisulfite PCR-LDR-qPCR assay for breast cancer detection.

BACKGROUND: Interrogation of site-specific CpG methylation in circulating tumor DNAs (ctDNAs) has been employed in a number of studies for early detection of breast cancer (BrCa). In many of these studies, the markers were identified based on known biology of BrCa progression, and interrogated using methyl-specific PCR (MSP), a technique involving bisulfite conversion, PCR, and qPCR. METHODS: In this report, we are demonstrating the development of a novel assay (Multiplex Bisulfite PCR-LDR-qPCR) which can potentially offer improvements to MSP, by integrating additional steps such as ligase detection reaction (LDR), methylated CpG target enrichment, carryover protection (use of uracil DNA glycosylase), and minimization of primer-dimer formation (use of ribose primers and RNAseH2). The assay is designed to for breast cancer-specific CpG markers identified through integrated analyses of publicly available genome-wide methylation datasets for 31 types of primary tumors (including BrCa), as well as matching normal tissues, and peripheral blood. RESULTS: Our results indicate that the PCR-LDR-qPCR assay is capable of detecting ~ 30 methylated copies of each of 3 BrCa-specific CpG markers, when mixed with excess amount unmethylated CpG markers (~ 3000 copies each), which is a reasonable approximation of BrCa ctDNA overwhelmed with peripheral blood cell-free DNA (cfDNA) when isolated from patient plasma. The bioinformatically-identified CpG markers are located in promoter regions of NR5A2 and PRKCB, and a non-coding region of chromosome 1 (upstream of EFNA3). Additional bioinformatic analyses would reveal that these methylation markers are independent of patient race and age, and positively associated with signaling pathways associated with BrCa progression (such as those related to retinoid nuclear receptor, PTEN, p53, pRB, and p27). CONCLUSION: This report demonstrates the potential utilization of bisulfite PCR-LDR-qPCR assay, along with bioinformatically-driven biomarker discovery, in blood-based BrCa detection.

Exuberant Squamous Metaplasia with Calcification Following Intraoperative Radiotherapy for Breast Carcinoma: Report of an Unusual Case and Retrospective Review of Cases from a Single Institution.

Intraoperative radiotherapy (IORT) is a novel and increasingly utilized radiation technique in the treatment of breast carcinoma. There are few reports on the histologic changes seen in breast tissue from patients who have undergone IORT. We sought to evaluate the histologic changes observed in specimens received following IORT, as well as report an unusual case which prompted our study. A retrospective review of patients who received IORT and subsequently had breast tissue histologically evaluated at our institution was performed. Fifteen post-IORT specimens from 12 patients, including the patient from the reported case, were studied. We report a case of a 77-year-old woman found to have mammographic microcalcifications at the lumpectomy site 6 months following lumpectomy and IORT for ductal carcinoma in situ (DCIS). A stereotactic biopsy showed abundant desquamated anucleate squamous cells with calcification and keratin material associated with squamous metaplasia of ducts. Carcinoma was not present. The predominant findings in the post-IORT specimens were fat necrosis and scar (n = 5), recurrent invasive carcinoma (n = 5), surgical site changes (n = 3), abscess (n = 1), and exuberant squamous metaplasia with calcification (n = 1). Five of fifteen (33%) post-IORT specimens showed squamous metaplasia, all of which were collected within 6 months of IORT delivery. The morphologic changes observed after IORT are similar to those seen after external beam radiotherapy. Exuberant squamous metaplasia is an uncommon consequence of IORT; however, pathologists should be aware of this phenomenon and review a history of prior intraoperative radiation before raising concern for malignancy.

Nipple Resection and Reconstruction After Attempted Nipple-Sparing Mastectomy.

BACKGROUND: Occult nipple malignancy is detected in 0% to 58% of attempted nipple-sparing mastectomies (NSM), prompting excision of the nipple. We report our experience with nipple resection following attempted NSM and our outcomes with subsequent nipple reconstruction. METHODS: An institutional review board-approved retrospective review was performed of attempted NSM cases with immediate implant-based reconstruction from July 2006 to April 2015. Patients who underwent nipple excision were identified. Indications for excision, pathology reports, and reconstructive outcomes were reviewed. RESULTS: Five hundred sixty-eight NSMs were performed in 330 patients. Thirty-four (6%) cases underwent nipple excision, 53% for positive frozen sections, 29% for positive permanent sections, 3% for clinical suspicion, and 15% either at patient request or for symmetry. All of the cases with positive frozen sections had disease on permanent section and 56% had residual disease in the resection specimen. Of the cases with positive permanent sections, frozen sections were negative in 50%, suspicious or atypical in 30%, and not sent in 20% of cases. Thirty percent had residual disease in the resection specimen. Frozen section sensitivity was 64% (or 75% if suspicious and atypical findings are included). There were no false-positive results on frozen section. Sixty-eight percent of cases have undergone nipple reconstruction by CV flap (57%), skate flap (39%), or nipple-sharing technique (4%). The aesthetic result after reconstruction was excellent in 83% of cases. CONCLUSIONS: Our findings support the benefit of intraoperative subareolar frozen section for detection of occult disease. When nipple excision is required, patients can still achieve an excellent aesthetic result with reconstruction.

Oncologic Outcomes After Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) is increasingly used as an alternative to traditional mastectomy because it provides improved aesthetic results. The data on its oncologic safety are limited. The authors' institution has performed NSM during the past 10 years for both oncologic and prophylactic indications. This study aimed to examine oncologic outcomes after NSM for breast cancer. METHODS: The study retrospectively examined all NSM cases managed between July 2007 and July 2013. Descriptive statistics were used to characterize the study cohort. Kaplan-Meier survival analysis was performed to estimate recurrence-free survival, specifically the 36-month recurrence-free survival proportion. RESULTS: A total of 721 nipple-sparing mastectomies were performed for 413 patients: 45 (10.9 %) to reduce risk and 368 (89.1 %) for breast cancer. In the breast cancer group, 29.8 % of the patients had ductal carcinoma in situ, and 70.2 % had invasive cancer. The mean follow-up time was 32 months (range 0.01-90.2 months). In the breast cancer group, the Kaplan-Meier 3-year recurrence-free survival rate was 93.6 % (95 % confidence interval, 89.9-96.0 %). Eight patients (2.2 %) had locoregional recurrences, including one in the nipple. Nine patients (2.4 %) had distant recurrence, and six patients (1.6 %) had a diagnosis of both local and distant recurrences. CONCLUSIONS: The findings showed a locoregional recurrence rate of 2.2 %, with an overall recurrence rate of 6.3 % for patients undergoing NSM for the treatment of breast cancer. The majority of these recurrences were distant, with one recurrence at the nipple. These results are promising, but a longer follow-up evaluation of this cohort is necessary.

Nipple-sparing mastectomy via an inframammary fold incision for patients with scarring from prior lumpectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) through an inframammary fold (IMF) incision can provide superior cosmesis and a high level of patient satisfaction. Because of concerns for nipple-areolar complex (NAC) viability using this incision, selection criteria may be limited. Here, we evaluate the impact of scarring from prior lumpectomy on NAC viability. METHODS: A retrospective chart review was conducted on a prospectively collected database at a single institution between July 2006 and October 2012. A total of 318 NSMs through IMF incisions were performed. We compared the incidence of NAC ischemia in 122 NSM cases with prior lumpectomy with 196 NSM cases without prior lumpectomy. All 318 mastectomies were followed by implant-based reconstruction. Clinicopathologic factors analyzed included indications for surgery, technical details, patient demographics, comorbidities, and adjuvant therapy. RESULTS: The overall incidence of NAC ischemia was 20.4% (65/318). Nipple-areolar complex ischemia occurred in 24.6% (30/122) of cases with prior lumpectomy and 17.9% (35/196) of cases without prior lumpectomy (P = 0.1477). Among the 30 ischemic events in the 122 cases with prior lumpectomy, epidermolysis occurred in 20 (16.4%) and necrosis occurred in 10 (8.2%). Two cases (1.6%) required operative debridement. Seven cases (5.7%) were left with areas of residual NAC depigmentation. All other cases completely resolved with conservative management. There was no significant correlation between the incidence of ischemia and surgical indication, tumor staging, age, body mass index, tissue resection volume, sternal notch to nipple distance, prior radiation, single-stage reconstruction, sentinel or axillary lymph node dissection, acellular dermal matrix use, presence of periareolar lumpectomy scars, diabetes, or smoking history. At a mean follow-up of 505 days (range, 7-1504 days), patient satisfaction was excellent. Local recurrence of breast cancer occurred in 3 cases (2.5%), and distant recurrence occurred in 2 cases (1.6%). CONCLUSIONS: Patients with scarring from prior lumpectomy do not have a higher rate of NAC ischemia and may be considered for NSM via an IMF incision.

A Comparative Retrospective Analysis of Complications After Oncoplastic Breast Reduction and Breast Reduction for Benign Macromastia: Are These Procedures Equally Safe?

INTRODUCTION: Oncoplastic breast reduction has been shown to be an effective approach to breast conservation surgery in women with macromastia. Clear surgical margins can be achieved while simultaneously improving symptomatic macromastia and enhancing aesthetic outcomes. Little has been written about postoperative complications after this procedure, beyond the risk of locoregional recurrence. This study aimed to compare the complication profile for oncoplastic breast reduction versus reduction for benign macromastia. METHODS: A retrospective review of our experience with oncoplastic breast reduction was performed. This represented a consecutive series of 118 patients undergoing bilateral breast reduction during the 7-year study period from March 2005 to March 2012. There were 64 patients identified who underwent oncoplastic breast reduction. Patients were determined to be a good candidate for breast conservation therapy if it was felt that clear surgical margins could be obtained without mastectomy. Postoperative complications (within 6 weeks of surgery) were compared to a control group of 56 patients undergoing reduction for benign macromastia. The associations between complications and potential risk factors were analyzed using logistic regression. RESULTS: Patients undergoing oncoplastic breast reduction and reduction for benign macromastia had some key differences. In general, macromastia patients were younger (mean age, 42.3 vs 57.5 years; P < 0.001) and had lower body mass index (mean, 26.1 vs 30.6 kg/m2; P < 0.001) compared to those patients having oncoplastic reduction. Within the oncoplastic reduction group, 14 (21.9%) patients had a total of 16 complications; among the benign macromastia group, 9 (16.1%) patients had a total of 10 complications (P = 0.420). On univariate analysis, oncoplastic reduction was not predictive of having a perioperative complication (odds ratio, 1.462; 95% confidence interval, 0.579-3.696; P = 0.422). Body mass index was found to be predictive of having a complication after reduction for either indication (odds ratio, 1.108; 95% confidence interval, 1.018-1.206; P = 0.017). Within the oncoplastic reduction cohort at an average follow-up of 34.6 months (range, 0.3-90.3 months), 5 (7.9%) patients developed locoregional recurrence and 2 patients developed distant metastasis. CONCLUSIONS: Compared with reduction mammoplasty for benign macromastia, a widely accepted procedure, patients undergoing oncoplastic breast reduction were equally likely to have a postoperative complication. Elevated body mass index was shown to be a statistically significant predictor of having a complication after reduction for either indication. Overall complication rates were acceptably low for both procedures.

Nipple-Sparing Mastectomy via an Inframammary Fold Incision with Implant-Based Reconstruction in Patients with Prior Cosmetic Breast Surgery.

BACKGROUND: Nipple-sparing mastectomy through an inframammary fold incision (NSM-IMF) with implant-based reconstruction (IBR) is a cosmetically preferable approach to breast cancer treatment in appropriate candidates. However, patients who have undergone prior cosmetic breast surgery (CBS) may be at increased risk for postoperative complications secondary to existing surgical scars. OBJECTIVE: To assess whether prior CBS increases the risk of complications following NSM-IMF with IBR. METHODS: A retrospective chart review was conducted for 398 NSM-IMFs with IBR performed between July 2006 and December 2013. CBS cases were identified. Outcomes were reviewed. RESULTS: Of 398 NSM-IMF cases, 41 had prior CBS: 24 augmentations, 12 reductions, three mastopexies, and two augmentation mastopexies. NSM-IMF was performed an average of 8 years following CBS. CBS cases had lower BMIs (P = .040), more breast tissue resected (P = .021), wider breast bases (P = .0002), more single-stage reconstructions (P < .0001), more ADM use (P < .0001), and larger permanent implants (P = .0051) than those without CBS. Postoperatively, CBS cases had higher rates of mastectomy flap ischemia (P = .0392) and hematoma (P = .0335). Among CBS cases, single-stage reconstruction was associated with increased full-thickness flap ischemia (P = .0066). Compared to prior augmentation cases, prior reduction/mastopexy cases had higher rates of capsular contracture (P = .0409) and seroma (P = .0226). CONCLUSIONS: This series is the largest to date to evaluate the success of NSM-IMF with IBR in CBS patients. These women should be cautiously considered for IBR, particularly in the setting of single-stage reconstruction. LEVEL OF EVIDENCE: 4 Therapeutic.

Recurrent breast cancer in the subpectoral space after implant reconstruction.

Breast reconstruction after mastectomy is most commonly performed with a prosthetic implant placed beneath the pectoralis major. Recurrence may rarely be identified in the subpectoral space where the implant was placed. We report a case of recurrent breast cancer after implant-based reconstruction with isolated subpectoral recurrence discovered 5 years later during secondary revision of her reconstructed breast.

Pathological evaluation of nipple-sparing mastectomies with emphasis on occult nipple involvement: the Weill-Cornell experience with 325 cases.

Nipple-sparing mastectomy (NSM) is an increasingly utilized surgical option in managing breast carcinoma; however, data on malignant involvement of a separately submitted nipple margin are scant. Consecutive NSM, including those performed for therapeutic and prophylactic purposes, over a 4-year period (2007-2011), were studied. A separately submitted nipple margin was evaluated by permanent H&E preparations and via frozen section evaluation whenever requested. 325 consecutive NSM specimens, 208 (64%) therapeutic-NSM, and 117 (36%) prophylactic-NSM were studied. All nipples were clinically unremarkable. 86% (179/208) of nipple margins from therapeutic-NSM and 100% (117/117) from prophylactic-NSM showed no histopathologic abnormality. 14% (29/208) of nipple margins from therapeutic-NSM and no nipple margin from prophylactic-NSM showed malignancy. Frozen section evaluation was performed in 188/325 NSM (58%) with a sensitivity of 64% and specificity of 99%. Central tumor location and stage N2/N3 lymph node status were significantly associated with nipple margin positivity (χ(2) ≤ 0.05). Subsequent nipple resection was performed in 69% (20/29) of nipple margin-positive cases with residual malignancy found in 40% (8/20, including three cases of invasive carcinoma). In a mean follow-up of 33 months, one invasive carcinoma recurred in the "saved" nipple, 36 months after therapeutic-NSM. 14% (29/208) of nipple margins in therapeutic-NSM and no nipple margin (0/117) in prophylactic-NSM showed malignancy. Central tumor location and N2/N3 stage were significantly associated with nipple margin positivity (χ(2) ≤ 0.05).

Immediate implant breast reconstruction with acellular dermal matrix for treatment of a large recurrent malignant phyllodes tumor.

UNLABELLED: Phyllodes tumors (PT) are rare fibroepithelial breast tumors representing less than 1 % of all breast malignancies. These tumors are unpredictable and fast growing with a high local recurrence rate, making this disease challenging to treat. Previous literature focused on surgical resection, and breast reconstruction following a mastectomy in patients with PT is rarely addressed. We report a case of a recurrent malignant PT treated with a nipple-sparing mastectomy followed by immediate single-stage silicone implant breast reconstruction. While PT is a rare breast malignancy that presents challenges with both surgical resection and reconstruction, we demonstrate that nipple-sparing mastectomy with immediate implant breast reconstruction with AlloMax is curative and can offer an appealing cosmetic option. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Nipple-areolar complex ischemia after nipple-sparing mastectomy with immediate implant-based reconstruction: risk factors and the success of conservative treatment.

BACKGROUND: Nipple-sparing mastectomy performed via an inframammary fold incision with implant-based reconstruction is an oncologically safe procedure that provides excellent cosmesis. OBJECTIVES: The authors report their experience with conservative treatment of postoperative nipple-areolar complex (NAC) ischemia and an analysis of risk factors for NAC ischemia and conservative treatment failure. METHODS: A retrospective chart review was conducted of 318 nipple-sparing mastectomies performed through inframammary fold incisions with implant-based reconstruction between July 2006 and October 2012. NAC dressings consisted of topical nitroglycerin, external warming for 24 hours, antibacterial petrolatum gauze, and a loose bra for 1 week. Patients were monitored for NAC ischemia as the primary endpoint. NAC ischemia was treated with bacitracin ointment. In cases of full-thickness ischemia, expanders were also partially deflated. RESULTS: Partial- and full-thickness NAC ischemia occurred in 44 (13.8%) and 21 (6.6%) cases, respectively. All partial- and 17 full-thickness cases resolved with conservative treatment. Of these, 7 partial- and 2 full-thickness cases suffered residual depigmentation. Four full-thickness cases required operative debridement. Factors associated with NAC ischemia included increasing age (P = .035), higher body mass index (P = .0009), greater breast volume (P = .0023), and diabetes (P = .0046). Factors associated with conservative treatment failure included increasing age (P < .0001), higher body mass index (P = .014), greater breast volume (P = .020), smoking (P = .0449), acellular dermal matrix use (P < .0001), and single-stage reconstruction (P = .0090). CONCLUSIONS: Postoperative NAC ischemia can be effectively managed conservatively to preserve cosmesis and implant viability. Knowledge of risk factors for NAC ischemia and conservative treatment failure may improve future patient counseling and outcomes.

Pregnancy-Associated Breast Changes after Nipple-Sparing Mastectomy.

BACKGROUND: Women of reproductive age are chronically underrepresented in breast cancer studies. Recent studies suggest that almost 40% of patients diagnosed with breast cancer who are of reproductive age want to have children after completing treatment. In this study, the authors evaluated patients of reproductive age who had undergone nipple-sparing mastectomy (NSM) and implant-based reconstruction. The authors compared those who became pregnant with those who did not with respect to clinical and radiologic changes that are reported at follow-up. METHODS: Any patient 45 years of age or younger at the time of NSM was determined to be of reproductive age, selected for evaluation, and followed prospectively. The presence or absence of breast examination changes in the setting of pregnancy after NSM was recorded. RESULTS: A total of 36 patients became pregnant after NSM, and 158 patients did not become pregnant after NSM. Of those who became pregnant, nearly half reported some clinical change just before or immediately after delivery. These changes included color change and discharge at the residual nipple-areola complex and palpable nodularity elsewhere. For those with palpable changes, an ultrasound was performed and hypoechoic lesions with variable vascularity were identified. For those who went on to excision, lactational hyperplasia was the most common diagnosis. CONCLUSIONS: Ultrasound is an appropriate first-line investigation of breast changes, which can include hyperplasia of remaining ductal and glandular tissue. Patients who became pregnant after NSM commonly had clinical breast examination changes, but the majority of these changes were found to be benign on further evaluation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Incremental increase in VEGFR1⁺ hematopoietic progenitor cells and VEGFR2⁺ endothelial progenitor cells predicts relapse and lack of tumor response in breast cancer patients.

Animal models have demonstrated the critical role of bone marrow-derived VEGFR1(+) hematopoietic progenitor cells (HPCs) and VEGFR2(+) endothelial progenitor cells (EPCs) in metastatic progression. We explored whether these cells could predict relapse and response in breast cancer (BC) patients. One hundred and thirty-two patients with stages 1-4 BC were enrolled on 2 studies. Circulating CD45(+)/CD34(+)/VEGFR1(+) HPCs and CD45(dim)/CD133(+)/VEGFR2(+) EPCs were assessed from peripheral blood mononuclear cells using flow cytometry. Changes in HPCs and EPCs were analyzed in (1) patients without overt disease that relapsed and (2) metastatic patients according to response by RECIST. At study entry, 102 patients were without evidence of disease and 30 patients had metastatic BC. Seven patients without evidence of BC by exam, labs, and imaging developed recurrence while on study. Median HPC/ml (range) increased from 645.8 (23.5-1,914) to 2,899 (1,176-37,336), P = 0.016, followed by an increase in median EPC/ml from 21.3 (4.7-42.5) to 94.7 (28.2-201.3), P = 0.016, prior to clinical relapse. In metastatic patients with progressive disease, median HPC/ml increased from 1,696 (10-16,470) to 5,124 (374-77,605), P = 0.0009, and median EPC/ml increased from 26 (0-560) to 71 (0-615) prior to progression, P = 0.10. In patients with responding disease, median HPC/ml decreased from 6,147 (912-85,070) to 633 (47-18,065), P = 0.05, and EPC/ml decreased from 46 (0-197) to 23 (0-105), P = 0.41, at response. There were no significant changes in these cells over time in patients with stable disease. Circulating bone marrow-derived HPCs and EPCs predict relapse and disease progression in BC patients.