RESUMEN
Stemming from breast density notification legislation in Massachusetts effective 2015, we sought to develop a collaborative evidence-based approach to density notification that could be used by practitioners across the state. Our goal was to develop an evidence-based consensus management algorithm to help patients and health care providers follow best practices to implement a coordinated, evidence-based, cost-effective, sustainable practice and to standardize care in recommendations for supplemental screening. We formed the Massachusetts Breast Risk Education and Assessment Task Force (MA-BREAST) a multi-institutional, multi-disciplinary panel of expert radiologists, surgeons, primary care physicians, and oncologists to develop a collaborative approach to density notification legislation. Using evidence-based data from the Institute for Clinical and Economic Review, the Cochrane review, National Comprehensive Cancer Network guidelines, American Cancer Society recommendations, and American College of Radiology appropriateness criteria, the group collaboratively developed an evidence-based best-practices algorithm. The expert consensus algorithm uses breast density as one element in the risk stratification to determine the need for supplemental screening. Women with dense breasts and otherwise low risk (<15% lifetime risk), do not routinely require supplemental screening per the expert consensus. Women of high risk (>20% lifetime) should consider supplemental screening MRI in addition to routine mammography regardless of breast density. We report the development of the multi-disciplinary collaborative approach to density notification. We propose a risk stratification algorithm to assess personal level of risk to determine the need for supplemental screening for an individual woman.
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Neoplasias de la Mama/diagnóstico , Detección Precoz del Cáncer , Medicina Basada en la Evidencia/legislación & jurisprudencia , Glándulas Mamarias Humanas/anomalías , Algoritmos , Densidad de la Mama , Manejo de la Enfermedad , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/normas , Medicina Basada en la Evidencia/normas , Femenino , Humanos , Imagen por Resonancia Magnética , Mamografía , Massachusetts , Medición de Riesgo , Ultrasonografía MamariaRESUMEN
Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve the sentinel lymph node (SLN) procedure by facilitating percutaneous and intraoperative identification of lymphatic channels and SLNs. Previous studies suggested that a dose of 0.62 mg (1.6 mL of 0.5 mM) ICG is optimal for SLN mapping in breast cancer. The aim of this study was to evaluate the diagnostic accuracy of NIR fluorescence for SLN mapping in breast cancer patients when used in conjunction with conventional techniques. Study subjects were 95 breast cancer patients planning to undergo SLN procedure at either the Dana-Farber/Harvard Cancer Center (Boston, MA, USA) or the Leiden University Medical Center (Leiden, the Netherlands) between July 2010 and January 2013. Subjects underwent the standard-of-care SLN procedure at each institution using (99)Technetium-colloid in all subjects and patent blue in 27 (28 %) of the subjects. NIR fluorescence-guided SLN detection was performed using the Mini-FLARE imaging system. SLN identification was successful in 94 of 95 subjects (99 %) using NIR fluorescence imaging or a combination of both NIR fluorescence imaging and radioactive guidance. In 2 of 95 subjects, radioactive guidance was necessary for initial in vivo identification of SLNs. In 1 of 95 subjects, NIR fluorescence was necessary for initial in vivo identification of SLNs. A total of 177 SLNs (mean 1.9, range 1-5) were resected: 100 % NIR fluorescent, 88 % radioactive, and 78 % (of 40 nodes) blue. In 2 of 95 subjects (2.1 %), SLNs-containing macrometastases were found only by NIR fluorescence, and in one patient this led to upstaging to N1. This study demonstrates the safe and accurate application of NIR fluorescence imaging for the identification of SLNs in breast cancer patients, but calls into question what technique should be used as the gold standard in future studies.
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Neoplasias de la Mama/patología , Rayos Infrarrojos , Metástasis Linfática/diagnóstico , Metástasis Linfática/patología , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Diagnóstico por Imagen/métodos , Femenino , Fluorescencia , Humanos , Verde de Indocianina , Ganglios Linfáticos/diagnóstico por imagen , Vasos Linfáticos/patología , Persona de Mediana Edad , RadiografíaRESUMEN
Whether wide excision with margins ≥1 cm is sufficient treatment for small low- or intermediate-grade ductal carcinoma in situ (DCIS) is unclear. This is an updated analysis of a phase II, single-arm, prospective trial testing this hypothesis. A total of 158 patients with low- or intermediate-grade DCIS who underwent wide excision alone (without radiation or tamoxifen) were entered onto the trial from 1995 to 2002. Entry criteria included mammographic extent ≤2.5 cm, predominantly low or intermediate nuclear grade, and excision with final microscopic margins ≥1 cm. Eight-year minimum potential follow-up was required for inclusion in the analysis; the final population comprised 143 patients. Cumulative incidence curves were generated to assess rates of local recurrence (LR) or other events. Median follow-up time was 11 years. Nineteen patients (13 %) had LR as a first event within 8 years. Thirteen LR (68 %) were DCIS only and six (32 %) were invasive. Fourteen (74 %) occurred in the original quadrant. The 10-year estimated cumulative incidence of LR was 15.6 %. The estimated annual percentage rate of LR was 1.9 % per patient-year. With longer follow-up, there remains a substantial and ongoing risk of LR in patients with favorable DCIS treated with wide excision margins without radiation. This information should be useful as patients and clinicians weigh the options of wide excision with and without radiation.
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Neoplasias de la Mama/cirugía , Carcinoma Intraductal no Infiltrante/cirugía , Mastectomía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/epidemiología , Carcinoma Intraductal no Infiltrante/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Estudios Prospectivos , Resultado del TratamientoRESUMEN
We sought to assess whether a close surgical margin (>0 and <2 mm) after breast-conserving therapy (BCT) confers an increased risk of local recurrence (LR) compared with a widely negative margin (≥2 mm). We studied 906 women with early-stage invasive breast cancer treated with BCT between January 1998 and October 2006; 91 % received adjuvant systemic therapy. Margins were coded as: (1) widely negative (n = 729), (2) close (n = 85), or (3) close (n = 84)/positive (n = 8) but having no additional tissue to remove according to the surgeon. Cumulative incidence of LR and distant failure (DF) were calculated using the Kaplan-Meier method. Gray's competing-risk regression assessed the effect of margin status on LR and Cox proportional hazards regression assessed the effect on DF, controlling for biologic subtype, age, and number of positive lymph nodes (LNs). Three hundred seventy-seven patients (41.6 %) underwent surgical re-excision, of which 63.5 % had no residual disease. With a median follow-up of 87.5 months, the 5-year cumulative incidence of LR was 2.5 %. The 5-year cumulative incidence of LR by margin status was 2.3 % (95 % CI 1.4-3.8 %) for widely negative, 0 % for close, and 6.4 % (95 % CI 2.7-14.6 %) for no additional tissue, p = 0.3. On multivariate analysis, margin status was not associated with LR; however, triple-negative subtype (AHR 3.7; 95 % CI 1.6-8.8; p = 0.003) and increasing number of positive LNs (AHR 1.6; 95 % CI 1.1-2.3; p = 0.025) were associated. In an era of routine adjuvant systemic therapy, close surgical margins and maximally resected close/positive margins were not associated with an increased risk of LR compared to widely negative margins. Additional studies are needed to confirm this finding.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Adulto , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Humanos , Estimación de Kaplan-Meier , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasia Residual/cirugía , Modelos de Riesgos ProporcionalesRESUMEN
INTRODUCTION: Women who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC. METHODS: Cultures of MECs were used to examine EGFR protein levels and promoter activity in response to BRCA1 suppression with inhibitory RNA. EGFR was assessed by immunoblot and immunofluorescence analysis, real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR) and flow cytometry. Binding of epidermal growth factor (EGF) to subpopulations of MECs was examined by Scatchard analysis. The responsiveness of MECs to the EGFR inhibitor erlotinib was assessed in vitro in three-dimensional cultures and in vivo. Mouse mammary tumor virus-Cre recombinase (MMTV-Cre) BRCA1flox/flox p53âº/â» mice were treated daily with erlotinib or vehicle control, and breast cancer-free survival was analyzed using the Kaplan-Meier method. RESULTS: Inhibition of BRCA1 in MECs led to upregulation of EGFR with an inverse correlation of BRCA1 with cellular EGFR protein levels (r² = 0.87) and to an increase in cell surface-expressed EGFR. EGFR upregulation in response to BRCA1 suppression was mediated by transcriptional and posttranslational mechanisms. Aldehyde dehydrogenase 1 (ALDH1)-positive MECs expressed higher levels of EGFR than ALDH1-negative MECs and were expanded two- to threefold in the BRCA1-inhibited MEC population. All MECs were exquisitely sensitive to EGFR inhibition with erlotinib in vitro. EGFR inhibition in MMTV-Cre BRCA1flox/flox p53âº/â» female mice starting at age 3 months increased disease-free survival from 256 days in the controls to 365 days in the erlotinib-treated cohort. CONCLUSIONS: We propose that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction. Increased EGFR expression may confer a growth advantage to MECs with loss of BRCA1 at the earliest stages of transformation. Employing EGFR inhibition with erlotinib specifically at this premalignant stage was effective in decreasing the incidence of ER-negative breast tumors in this mouse model.
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Proteína BRCA1/metabolismo , Mama/metabolismo , Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , Genes BRCA1 , Neoplasias Mamarias Experimentales/prevención & control , Familia de Aldehído Deshidrogenasa 1 , Animales , Mama/citología , Línea Celular Tumoral , Transformación Celular Neoplásica , Células Cultivadas , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Genes p53 , Humanos , Isoenzimas/metabolismo , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Virus del Tumor Mamario del Ratón , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Interferencia de ARN , Receptores de Estrógenos/metabolismo , Retinal-Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: Near-infrared (NIR) fluorescent sentinel lymph node (SLN) mapping in breast cancer requires optimized imaging systems and lymphatic tracers. MATERIALS AND METHODS: A small, portable version of the FLARE imaging system, termed Mini-FLARE, was developed for capturing color video and two semi-independent channels of NIR fluorescence (700 and 800 nm) in real time. Initial optimization of lymphatic tracer dose was performed using 35-kg Yorkshire pigs and a 6-patient pilot clinical trial. More refined optimization was performed in 24 consecutive breast cancer patients. All patients received the standard of care using (99m)Technetium-nanocolloid and patent blue. In addition, 1.6 ml of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected directly after patent blue at the same location. Patients were allocated to 1 of 8 escalating ICG:HSA concentration groups from 50 to 1000 µM. RESULTS: The Mini-FLARE system was positioned easily in the operating room and could be used up to 13 in. from the patient. Mini-FLARE enabled visualization of lymphatic channels and SLNs in all patients. A total of 35 SLNs (mean = 1.45, range 1-3) were detected: 35 radioactive (100%), 30 blue (86%), and 35 NIR fluorescent (100%). Contrast agent quenching at the injection site and dilution within lymphatic channels were major contributors to signal strength of the SLN. Optimal injection dose of ICG:HSA ranged between 400 and 800 µM. No adverse reactions were observed. CONCLUSIONS: We describe the clinical translation of a new NIR fluorescence imaging system and define the optimal ICG:HSA dose range for SLN mapping in breast cancer.
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Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Intraductal no Infiltrante/diagnóstico por imagen , Carcinoma Lobular/diagnóstico por imagen , Vasos Linfáticos/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Colorantes , Femenino , Fluorescencia , Humanos , Procesamiento de Imagen Asistido por Computador , Verde de Indocianina , Ganglios Linfáticos , Metástasis Linfática , Vasos Linfáticos/patología , Vasos Linfáticos/cirugía , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Cintigrafía , Radiofármacos , Biopsia del Ganglio Linfático Centinela , Espectroscopía Infrarroja Corta , PorcinosRESUMEN
Clinical translation of scientific discoveries is often the long-term goal of academic medical research. However, this goal is not always realized due to the complicated path between bench research and clinical use. In this review, we outline the fundamental steps required for first-in-human testing of a new imaging device, and use the FLARE() (Fluorescence-Assisted Resection and Exploration) near-infrared fluorescence optical imaging platform as an example.
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Ensayos Clínicos como Asunto , Diagnóstico por Imagen/tendencias , Óptica y Fotónica , Animales , Investigación Biomédica/normas , Investigación Biomédica/tendencias , Diagnóstico por Imagen/normas , Diseño de Equipo , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Garantía de la Calidad de Atención de Salud , Espectroscopía Infrarroja Corta/métodos , Tomografía Computarizada de Emisión de Fotón Único , Ultrasonografía , Rayos XRESUMEN
BACKGROUND: Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE imaging system overcomes this major obstacle. METHODS: Color video was acquired simultaneously, and in real-time, along with two independent channels of NIR fluorescence. Grayscale NIR fluorescence images were converted to visible "pseudo-colors" and overlaid onto the color video image. Yorkshire pigs weighing 35 kg (n = 5) were used for final preclinical validation of the imaging system. A six-patient pilot study was conducted in women undergoing sentinel lymph node (SLN) mapping for breast cancer. Subjects received (99m)Tc-sulfur colloid lymphoscintigraphy. In addition, 12.5 microg of indocyanine green (ICG) diluted in human serum albumin (HSA) was used as an NIR fluorescent lymphatic tracer. RESULTS: The FLARE system permitted facile positioning in the operating room. NIR light did not change the look of the surgical field. Simultaneous pan-lymphatic and SLN mapping was demonstrated in swine using clinically available NIR fluorophores and the dual NIR capabilities of the system. In the pilot clinical trial, a total of nine SLNs were identified by (99m)Tc- lymphoscintigraphy and nine SLNs were identified by NIR fluorescence, although results differed in two patients. No adverse events were encountered. CONCLUSIONS: We describe the successful clinical translation of a new NIR fluorescence imaging system for image-guided oncologic surgery.
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Neoplasias de la Mama/diagnóstico , Fluorometría/métodos , Verde de Indocianina , Ganglios Linfáticos/patología , Anciano , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Colorantes , Femenino , Fluorescencia , Humanos , Periodo Intraoperatorio , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática , Persona de Mediana Edad , Proyectos Piloto , Cintigrafía , Radiofármacos , Biopsia del Ganglio Linfático Centinela , Cirugía Asistida por Computador , Sus scrofa , Azufre Coloidal Tecnecio Tc 99mRESUMEN
Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1-positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n = 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERalpha; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploinsufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers.
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Proteína BRCA1/genética , Neoplasias de la Mama/genética , Diferenciación Celular/genética , División Celular/genética , Mutación , Adulto , Anciano , Aldehído Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Receptores ErbB/genética , Femenino , Tamización de Portadores Genéticos , Humanos , Inmunohistoquímica , Isoenzimas/genética , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Valores de Referencia , Retinal-Deshidrogenasa , Factores de Riesgo , Células Tumorales CultivadasRESUMEN
PURPOSE: It has been hypothesized that wide excision alone with margins > or = 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial. METHODS: Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of < or = 2.5 cm treated with wide excision with final margins of > or = 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients. RESULTS: In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease. CONCLUSION: Despite margins of > or = 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.