Faina Nakhlis

Molecular biology of breast metastasis The use of mathematical models to determine relapse and to predict response to chemotherapy in breast cancer

Breast cancer mortality rates have shown only modest improvemen despite the advent of effective chemotherapeutic agents which have been administered to a large percentage of women with breast cancer. In an effort to improve breast cancer treatment strategies, a variety of mathematical models have been developed that describe the natural history of breast cancer and the effects of treatment on the cancer. These models help researchers to develop, quantify, and test various treatment hypotheses quickly and efficiently. The present review discusses several of these models, with a focus on how they have been used to predict the initiation time of metastatic growth, the effect of operative therapy on the growth of metastases, and the optimal administration strategy for chemotherapy.

Can Methylene Blue Only Be Used in Sentinel Lymph Node Biopsy for Breast Cancer

Abstract:  Sentinel lymph node biopsy (SLNB) has become an accepted standard of care to stage the axilla for clinically node‐negative early stage breast cancer. In experienced hands, studies have shown an acceptable rate of identification of the sentinel lymph node (SLN) with blue dye only. Lymphazurin is occasionally associated with severe allergic reaction, including anaphylaxis and death. The use of methylene blue alone as a method of identifying the SLN in breast cancer has been reported once previously in the literature. Methylene blue may be an acceptable alternative with fewer deleterious side effects. Medical records of patients, who underwent sentinel node mapping between September 2003 and March 2005 by two surgeons at an academic medical center were reviewed. SLN mapping was performed by periareolar injection of 5 cc of 1% methylene blue. All patients with positive SLNs underwent completion axillary node dissection. During the study period, 141 consecutive patients with clinically node‐negative axillas and without evidence of inflammatory breast cancer underwent SLNB with injection of methylene blue only. A SLN was identified in 136 of 141 patients (96.5%). Thirty‐three of 136 SLNs (24%) harbored metastatic disease. No cases of anaphylaxis were noted. In experienced hands, methylene blue alone is a highly sensitive method of detecting SLNs. Avoiding the greater frequency of allergic reactions seen with lymphazurin is an important advantage of methylene blue.

Bevacizumab: where do we go from here in breast cancer?

Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor A, which received accelerated FDA approval in 2008 for first line treatment of HER2-negative metastatic breast cancer. The initial approval was based on studies suggesting a progression-free survival and not overall survival. This observation served as the basis for looking into the use of bevacizumab as an adjunct to neoadjuvant chemotherapy in the treatment of HER2-negative breast cancer.

Complex sclerosing lesions and radial sclerosing lesions on core needle biopsy: Low risk of carcinoma on excision in cases with clinical and imaging concordance

Complex or radial sclerosing lesions (CSL/RSL) are uncommon diagnoses on core needle biopsy with a reported upgrade rate ranging between 0% and 23%. As a result, their management remains controversial. In this study, we sought to determine the rate of malignancy on excision for patients with pure CSL/RSL on core biopsy, and to evaluate future breast cancer risk when CSL/RSL is managed without excision. We retrospectively reviewed 118 cases of CSL/RSL diagnosed on image‐guided breast biopsies between 2005 and 2014 at our institution. Of 98 analyzed patients, 34 (35%) underwent excision and 64 (65%) were observed. Demographic and clinical variables between excision and observation groups were compared. In excised specimens, factors associated with upgrade to malignancy were evaluated. The median age at diagnosis was 49 years (range, 27‐88 years). In the excision group, 3/34 cases were associated with malignancy, an overall upgrade rate of 9%. All malignant cases had core needle biopsies interpreted as discordant and were BIRADS 4B or more on imaging. In the observation group, at a median follow‐up of 2.2 years, 3/64 (5%) patients developed ipsilateral cancers, all of which were distant from the index CSL/RSL. In our series, we report a 9% malignancy rate on excision of BIRADS >4C lesions characterized as CSL/RSL on core biopsy. In patients with concordant biopsies and BIRADS 4A or lower lesions who underwent observation, we found a low rate of subsequent ipsilateral cancers. Further studies are needed to confirm that for CSL/RSL in concordant core biopsies and BIRADS 4A or lower, nonpalpable lesions, observation may be a reasonable alternative to excision.

Erratum to: Papilloma on Core Biopsy: Excision vs. Observation

Faina Nakhlis, Nasim Ahmadiyeh, Susan Lester, Sughra Raza, Parisa Lotfi, and Mehra Golshan Department of Surgery, Brigham and Womens Hospital, Boston; Department of Surgery, University of California, San Francisco, San Francisco; Department of Pathology, Brigham and Women’s Hospital, Boston; Radiology, Brigham and Women’s Hospital, Boston; Department of Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston

Molecular determinants of post-mastectomy breast cancer recurrence

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.Genomics: NF1 mutations more frequent in recurrent breast cancerWomen with breast cancer who relapse following surgery frequently harbor genomic alterations in a pathway linked to cell proliferation and anti-tumor immune responses. A USA-based team led by Funda Meric-Bernstam from the University of Texas MD Anderson Cancer Center in Houston, and Kimberly Keene from the University of Alabama at Birmingham conducted a thorough molecular analysis of tumor samples obtained from 115 women with 5 years of follow-up after a mastectomy and, oftentimes, adjuvant chemotherapy or hormonal therapy. RNA profiles did not significantly differ between women who experienced local recurrence, developed distant metastases or were still in remission. However, DNA analyses identified significantly more mutations in patients whom recurred in the mitogen-activated protein kinase cell signaling pathway, specifically NF1, implicated in cell growth and immunity. If validated, the findings support targeting this pathway to prevent disease recurrence.

Diagnostic Management of Papillomas, Radial Scars, and Flat Epithelial Atypia: Core Biopsy Alone Versus Core Biopsy Plus Excision

Intraductal papillomas, radial scars, and flat epithelial atypia (FEA) are common benign breast lesions diagnosed by core needle biopsy. There is debate over whether surgical excision is mandated for these lesions to rule out malignancy, or whether certain patients may be safely observed. This chapter summarizes the literature, discusses current management recommendations, and identifies areas for further investigation. Radial scars are usually excised due to difficulty establishing concordance. Certain intraductal papilloma subsets, including atypical, palpable, or multiple papillomas, should also be excised due to a high upgrade rate to malignancy. However, a growing body of evidence supports observation as a reasonable alternative in patients with a core biopsy diagnosis of benign solitary intraductal papillomas or pure FEA.

How Do We Approach Benign Proliferative Lesions

Purpose of ReviewThe aim of this review is to summarize recently published literature addressing atypical ductal hyperplasia (ADH), lobular neoplasia (atypical lobular hyperplasia [ALH] and classic lobular carcinoma in situ [C-LCIS]), non-classic lobular carcinoma in situ (NC-LCIS), papillary lesions, and flat epithelial atypia (FEA).Recent FindingsWhile ADH, ALN, and C-LCIS are well-established markers of an increased risk of future breast cancers, the risk implications are less clear for papillary lesions and FEA. NC-LCIS is the least well-characterized lesion, with scant published literature on its natural history and surgical management when encountered on needle biopsy.SummaryRecent data suggest that lobular neoplasia on core biopsy of a BI-RADS ≤ 4 concordant lesion does not require an excision, while ADH, atypical papillomas, and NC-LCIS should be excised. Evidence on FEA and papillomas without atypia suggests a low risk of upgrade on excision, and prospective studies on the upgrade of these lesions are ongoing.

Evaluating the risk of underlying malignancy in patients with pathologic nipple discharge

Most pathologic nipple discharge (PND) is benign, but duct excision has been advised to exclude malignancy. To identify factors associated with malignancy, we reviewed 280 patients with PND at our institution from 2004 to 2014. In 49 cases, malignancy was found. These patients more often had palpable masses (39% vs 11%, P < .001) and abnormal imaging (94% vs 75%, P = .004). On multivariable analysis, age, palpable mass, and abnormal imaging were independently associated with malignancy. Among 48 patients with PND but no other clinical/imaging abnormalities, only 1 malignancy, a small ductal carcinoma in situ, was identified. Observation may be reasonable for these select patients.

Abstract OT2-02-03: Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy

Background: Inflammatory breast cancer (IBC) continues to have a poor prognosis despite standard tri-modality treatment with chemotherapy, mastectomy and radiation. Current methods of assessing primary tumor response (i.e., clinical exam and breast magnetic resonance imaging [MRI]) are limited for distinguishing residual tumor from responsive disease because of persistent morphologic changes in the breast. Therefore, the inability to accurately assess tumor response during treatment often results in the continuation of ineffective systemic chemotherapy until definitive pathologic evaluation at mastectomy. IBC has a highly angiogenic phenotype which is believed to play a role in this tumor9s aggressiveness. The novel radiotracer Zirconium-89 ( 89 Zr)-bevacizumab was developed for imaging tumor angiogenesis with PET. We hypothesize that, as an imaging biomarker of angiogenesis, 89 Zr-bevacizumab-PET/CT is a more specific noninvasive functional imaging modality for detecting the presence of tumor angiogenesis compared to current diagnostic methods and will serve as a predictor of response to therapy in patients (pts) with IBC. Methods: Pts with newly diagnosed HER2neg IBC who will receive preoperative chemotherapy are eligible for this pilot study. 89 Zr-bevacizumab-PET/CT, breast MRI and FDG-PET/CT are performed before, after 2 cycles, and at the completion of preoperative therapy. Biopsies of primary IBC tumors are obtained prior to and after 2 cycles of preoperative therapy. At the completion of preoperative therapy, pts proceed to mastectomy or biopsy if ineligible to proceed to mastectomy based on current standards for assessing primary tumor response, i.e., clinical exam, breast MRI and lack of systemic progression. At the time of mastectomy, standard evaluation of the surgical specimen will determine pathologic response of IBC to preoperative chemotherapy. A research sample will be collected if residual cancer is present at the time of mastectomy for histologic evaluation of tumor angiogenesis. Objectives/Correlatives: The primary objective is to determine feasibility of 89 Zr-bevacizumab-PET/CT imaging in pts with IBC. The primary endpoint is assessment of radiolabeling of chelated bevacizumab and number of successfully acquired 89 Zr-bevacizumab-PET/CT scans. Correlative studies will be performed on IBC tissue to assess extent of angiogenesis including microvessel density, vessel diameter, vascular pericyte coverage and tumor VEGF levels. Secondary objectives are: 1) To determine if 89 Zr-bevacizumab accumulation in primary IBC tumors correlates with the extent of angiogenesis determined by correlative analysis on IBC tissue; 2) To assess the predictive value of 89 Zr-bevacizumab-PET/CT after 2 cycles and at the end of preoperative therapy for determining pathologic response at mastectomy as given by residual cancer burden. Statistics: This is an accrual, not statistical based, feasibility justification. Planned sample size is 10 in order to make a preliminary statement about feasibility and ability for 89 Zr-bevacizumab-PET/CT to serve as a surrogate in vivo biomarker of tumor angiogenesis and response to preoperative chemotherapy. Clinical Trial Information: NCT01894451 . Citation Format: Jacene HA, Overmoyer B, Schlosnagle EJ, Abbott A, Yeh E, Paolino J, Goel S, Culhane A, Bellon JR, Nakhlis F, Hirshfield-Bartek J, Van den Abbeele A. Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy [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 OT2-02-03.