Associations amongst genes, molecules, cells, and organs in breast cancer metastasis.

This paper is a cross fertilization of ideas about the importance of molecular aspects of breast cancer metastasis by basic scientists, a pathologist, and clinical oncologists at the Henry Ford Health symposium. We address four major topics: (i) the complex roles of lymphatic endothelial cells and the molecules that stimulate them to enhance lymph node and systemic metastasis and influence the anti-tumor immunity that might inhibit metastasis; (ii) the interaction of molecules and cells when breast cancer spreads to bone, and how bone metastases may themselves spread to internal viscera; (iii) how molecular expression and morphologic subtypes of breast cancer assist clinicians in determining which patients to treat with more or less aggressive therapies; (iv) how the outcomes of patients with oligometastases in breast cancer are different from those with multiple metastases and how that could justify the aggressive treatment of these patients with the hope of cure.

Revealing the concealed: A tribute to Donald L. Morton, MD.

Donald L. Morton, MD, epitomized one of America's dream scenarios: a person evolving from the humblest of origins to become an international celebrity in his profession, leading the world in the discipline of surgical oncology. His pioneering accomplishments in various roles have been well documented. Scientists, clinicians, students, and patients benefited from his contributions to the management of malignant diseases, particularly melanoma. His many attributes in pursuing the goal to cure malignant diseases are well known. Browsing the scientific literature reveals an almost unmatched publication record and continuous National Institutes of Health funding. He revealed dozens of original concealed ideas, not least of which is the tumor-draining regional lymph node, now called the sentinel lymph node (SLN). When others gave up on the original promise of immunotherapy, he saw the future, the clinical promise which has lately materialized in the control of previously untreatable malignancies. He regarded the fellowship-training of more than 100 surgical oncologists as one of his biggest achievements. In this article, we celebrate the human side of a man with creative courage and far-reaching insight.

Early breast cancer survival of black and white American women with equal diagnostic and therapeutic management.

PURPOSE: Breast cancer (BC) survival favors White versus Black Americans despite advances in screening and treatment. We hypothesized that these differences were dependent upon quality of care by analyzing long-term outcomes of 3139 early BC patients at our quaternary care center where uniform access and management of BC is provided to women irrespective of race. METHODS: Prospectively collected data for clinical stage I-II BC patients from our quaternary care cancer center were analyzed, focusing on disease-specific survival (DSS). Subgroup analyses included the overall cohort, triple-negative BC (TNBC), non-TNBC and HER2/neu positive patients. Multivariable analyses to evaluate associations of variables with DSS were performed for each subgroup. RESULTS: The overall cohort consisted of 3139 BC patients (1159 Black, 1980 White). Black and White patients did not differ by most baseline variables. Black patients had higher rates of TNBC (18% versus 10%, p < 0.0001). Kaplan-Meier analysis of all subgroups (overall, TNBC, non-TNBC, HER2/neu positive) did not reveal DSS differences between Black and White patients. Multivariable analysis of subgroups also did not find race to be associated with DSS. CONCLUSION: In this large, carefully controlled, long term, single-institution prospective cohort study DSS in Black and White early BC patients with equal access to high quality care, did not differ. While BC patients with adverse molecular markers did slightly worse than those with more favorable markers, there is no observable difference between Black and White women with the same markers. These observations support the conclusion that equal access to, and quality, of BC care abolishes racial disparities in DSS.

Mechanisms of breast cancer metastasis.

Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease. For example, if we had a drug that targeted a gene that is critical for metastasis, we might even be able to cure a vast majority of patients with breast cancer. By bringing together scientists with expertise in molecular aspects of breast cancer metastasis, and those with expertise in the mechanical aspects of metastasis, this paper probes interesting aspects of the metastasis cascade, further enlightening us in our efforts to improve the outcome from breast cancer treatments.

Clinicopathological Evaluation of the Potential Anatomic Pathways of Systemic Metastasis from Primary Breast Cancer Suggests an Orderly Spread Through the Regional Lymph Nodes.

BACKGROUND: Two conflicting hypotheses as to how breast cancer (BC) accesses the systemic circulation dominated the 20th century and affected surgical treatment. We hypothesized that tumor lymphovascular invasion (LVI) at the primary tumor site favors lymphatic and not blood vessel, capillaries, and systemic metastases (Smets) are dependent upon regional lymph node (RLN) mets. METHODS: Data from BC patients undergoing RLN biopsy was professionally abstracted and maintained in a prospective, precisely managed, single-institution database. Associations of RLN, LVI, and Smets were estimated by univariate and multivariate backward logistic regression models and patient-affiliated demographic, clinicopathologic, treatment type, and molecular marker data. RESULTS: Of 3329 patients, followed 1-22 years (mean 7.8), 463 of 3329 (13.9%) showed LVI, 742 of 3329 (22.3%) had RLN mets, and 262 of 3329 (7.9%) had Smets. Smets occurred in 52 of 252 (21% with LVI+/RLN+); 116 of 2301 (5% with LVI-/RLN-); 65 of 465 (14% with LVI-/RLN+); and 17 of 207 (8% with LVI+/RLN-), p = 0.021 for association between LVI and Smets for RLN+ patients but not for RLN- patients (p = 0.051). Positive RLN, larger tumor size, and higher grade (all p < 0.001) were predictive of Smets by the multivariable model, whereas positive LVI was not. CONCLUSIONS: LVI predicts RLN mets in BC. RLN is critical to Smets from BC, whereas LVI on its own is not. Smets occur significantly more commonly when both LVI and RLN mets occur together. LVI is, thus, likely to be primarily lymphatic invasion, and rarely, blood vessel invasion, supporting the Halsted paradigm. LVI and RLN together predict clinical outcome better than either alone.

Evaluation of a Multidisciplinary Team Approach for Generating Survivorship Care Plan Treatment Summaries in Patients With Breast Cancer.

INTRODUCTION: The optimal structure for survivorship care plan (SCP) programs and methodology for generating treatment summaries (TSs) has not yet been defined, but the Commission on Cancer and the National Accreditation Program for Breast Centers both mandate that participating oncology programs implement SCP-TS processes for patients that have completed treatment. METHODS: We used the Institute for Healthcare Improvement's Plan-Do-Study-Act model for conducting a quality improvement project evaluating two different SCP-TS programs implemented at the Henry Ford Health System/Henry Ford Cancer Institute's Breast Oncology Program in Detroit, Michigan. System I involved TSs drafted by nonspecialist breast clinic staff; System II involved TSs vetted through a multidisciplinary breast specialist conference approach. Accuracy of basic documentation entries related to dates and components of treatment were compared for the two approaches. RESULTS: Seventy-one System I and 93 System II documents were reviewed. Documentation was accurate in at least 90% of documents for both systems regarding delivery of chemotherapy and/or endocrine therapy and for documenting the identity of the various members of the cancer treatment team. Both systems had notable inaccuracies in documenting type of surgery performed, but System II had fewer inaccuracies than System I (33.78% v 51.67%, respectively; P = .05). System II, compared with System I, had fewer inaccuracies in documenting date of diagnosis (9.68% v 25.35%, respectively; P = .01) and had less missing information for dose of radiation delivered (9.33% v 33.9%, respectively; P < .01). CONCLUSION: A multidisciplinary team approach to drafting and reviewing SCP-TS documents improved content accuracy for our program, but ongoing education regarding documentation of various surgical procedures is warranted.

Distribution and Short-term Prognostic Value of the 21-gene recurrence score in African American compared to White American breast cancer patients.

We evaluated 328 patients (34.8% African American [AA]; 65.2% White American [WA]) with hormone receptor-positive, HER2/neu-negative breast cancer. Mean age (60 years); mean tumor size (1.6 and 1.7 cm for AA and WA, respectively) were similar, and mean BMI was higher for AA (33 vs 29.8; P = 0.001). Recurrence score (RS) distribution was similar- 8.3% AA and 5.9% WA with high RS (≥31). No significant differences were observed in delivery of chemotherapy stratified by score. With median follow-up 27.2 months for AA and 33.4 months for WA, distant recurrence occurred in 1.0% and 1.6%, respectively (P = 1). Our results suggest comparable RS utility in AA and WA patients.

Breast cancer metastasis through the lympho-vascular system.

Breast cancer metastasizes through the lymphovascular system to the regional lymph nodes in the axilla and to both visceral and non-visceral sites. Renewed interest in the route by which tumor cells gain access to blood and lymphatic capillaries are the subject of research at mechanical, anatomic, pathologic, genetic, epidemiologic and molecular levels. Two papers presented at the 7th International Symposium on Cancer Metastasis in San Francisco showed tumor cells entering the systemic circulation through the sentinel lymph node. This information challenges the current paradigm where clinicians believe that access is gained through intra- and peri-tumoral blood vessels and that metastasis to axillary lymph nodes is an interesting epi-phenomenon. The sentinel lymph node era has changed the modern surgical approach to the axilla and the basis of this change is summarized in this paper. A new approach to the management of axillary metastases after systemic therapy relies on determining whether there is a complete pathologic response; if no tumor is found in the previously biopsied node, a complete axillary lymph node dissection may be avoided. African American women seem to inherit a trait from West African ancestors and tend to develop more lethal types of breast cancer. These tumors may have a molecular machinery that enhances their ability to metastasize to visceral sites and future research may unearth the mechanisms for this phenomenon.

Utilization of the 21-Gene Recurrence Score in a Diverse Breast Cancer Patient Population: Development of a Clinicopathologic Model to Predict High-Risk Scores and Response to Neoadjuvant Chemotherapy.

INTRODUCTION: The 21-gene expression profile [Oncotype DX Recurrence Score (RS)] stratifies benefit from adjuvant chemotherapy in hormone receptor (HR)-positive, HER2/neu-negative, node-negative breast cancer. It is not routinely applied to predict neoadjuvant chemotherapy (NACT) response; data in diverse patient populations also are limited. We developed a statistical model based on standard clinicopathologic features to identify high-risk cases (RS > 30) and then evaluated ability of predicted high RS to predict for NACT downstaging. METHODS: Primary surgery patients with Oncotype DX RS testing 2012-2016 were identified from a prospectively-maintained database. A RS predictive model was created and applied to a dataset of comparable NACT patients. Response was defined as tumor size decrease ≥ 1 cm. RESULTS: Of 394 primary surgery patients-60.4% white American; 31.0% African American-RS distribution was similar for both groups. No single feature reliably identified high RS patients; however, a model accounting for age, HR expression, proliferative index (MIB1/Ki67), histology, and tumor size was generated, with receiver operator area under the curve 0.909. Fifty-six NACT patients were identified (25 African American). Of 21 cases with all relevant clinicopathology, 14 responded to NACT and the model generated high-risk RS in 14 (100%); conversely, of 16 cases generating high-risk RS, only 2 did not respond. CONCLUSIONS: Predictive modelling can identify high RS patients; this model also can identify patients likely to experience primary tumor downstaging with NACT. Until this model is validated in other datasets, we recommend that Oncotype-eligible patients undergo primary surgery with decisions regarding chemotherapy made in the adjuvant setting.

[Contribution of teledermatology in a hospital pediatrics department]. / Apport de la télédermatologie dans un service de pédiatrie hospitalière.

The hospital of Versailles no longer has a dermatologist; consequently the pediatrics department suggested assess to the system put in place in 2015 based on the telemedicine software platform WebDCR developed throughout the hospital. The acceptability of this was based on its implementation as well as speed and ease of use. METHODS: In 2015, 47 reviews were submitted. RESULTS: No patient refusal was noted. The answer was obtained in 100 % of cases on the day the requests were made, during the week. A diagnosis was made in 36 % of cases and one or more hypotheses were formulated in the 64 % of the remaining cases. The review resulted in a further consultation in 28 % of cases, and in one case to transfer to the dermatology department. The quality of the data collected was considered good or excellent in 96 % of cases. DISCUSSION: This first teledermatology experiment seems to show its utility in terms of the services provided. Given the successful deployment of the system, it was extended to the pediatric emergency department. The response time was reduced to 1h. CONCLUSION: This first teledermatology experiment seems to show its real value in terms of services rendered. However, it is necessary to have more experience to confirm the contribution of this tool, and to reassess the sustainability and economic relevance of the device.

[Teledermatology between two French hospitals: Two years of experience]. / Télédermatologie unissant deux hôpitaux : deux ans d'expérience.

BACKGROUND: Teledermatology is currently booming. Due to the shortage of dermatologists in hospitals access to dermatological consultations is very limited in some hospitals. We present our experience of collaboration between an expert center, the dermatology department of the Victor-Dupouy Hospital Centre in Argenteuil, and all medical structures under the André-Mignot Hospital in Versailles (CHV), including 2 prison medical centers (UCSA), traditional departments and emergency department. PATIENTS AND METHODS: Teledermatology, developed in the form of tele-expertise, began at the UCSA in November 2013. This expertise was then extended in June 2014 to the Internal Medicine department of CHV, and in December 2014 to all departments, including the emergency department. The rules and ethics of teledermatology were strictly adhered to. While UCSA could file all expertise dossiers, only urgent or difficult cases could be filed by other CHV departments. RESULTS: In 26 months, 347 expertise requests were filed: 231 by prisons and 116 by the other departments of the CHV. No patients refused teledermatology. The quality of information and photographs was considered good or excellent in over 95% of cases. A response was given within 3hours in more than 50% of cases and in all cases within 24hours (on working days). Analysis of diseases diagnosed illustrates the wide variety of conditions encountered in dermatology, with different structures having their own specific features. CONCLUSION: Our example illustrates the possibility of developing such an inter-hospital platform. However, it does not yet cater for requests made by patients to dermatologists, by dermatologists to dermatologists, or by dermatologists to the hospital teledermatology department. Acceptability was considered excellent by patients (with no refusals), physicians at the CHV, and the expert center.

Association Between Benign Breast Disease in African American and White American Women and Subsequent Triple-Negative Breast Cancer.

IMPORTANCE: Compared with white American (WA) women, African American (AA) women have a 2-fold higher incidence of breast cancers that are negative for estrogen receptor, progesterone receptor, and ERBB2 (triple-negative breast cancer [TNBC]). Triple-negative breast cancer, compared with non-TNBC, likely arises from different pathogenetic pathways, and benign breast disease (BBD) predicts future non-TNBC. OBJECTIVE: To determine whether AA identity remains associated with TNBC for women with a prior diagnosis of BBD. DESIGN, SETTING, AND PARTICIPANTS: This study is a retrospective analysis of data of a cohort of 2588 AA and 3566 WA women aged between 40 and 70 years with a biopsy-proven BBD diagnosis. The data-obtained from the Pathology Information System of Henry Ford Health System (HFHS), an integrated multihospital and multispecialty health care system headquartered in Detroit, Michigan-include specimens of biopsies performed between January 1, 1994, and December 31, 2005. Data analysis was performed from November 1, 2015, to June 15, 2016. MAIN OUTCOMES AND MEASURES: Subsequent breast cancer was stratified on the basis of combinations of hormone receptor and ERBB2 expression. RESULTS: Case management, follow-up, and outcomes received or obtained by our cohort of 2588 AA and 3566 WA patients were similar, demonstrating that HFHS delivered care equitably. Subsequent breast cancers developed in 103 (4.1%) of AA patients (mean follow-up interval of 6.8 years) and 143 (4.0%) of WA patients (mean follow-up interval of 6.1 years). More than three-quarters of subsequent breast cancers in each subset were ductal carcinoma in situ or stage I. The 10-year probability estimate for developing TNBC was 0.56% (95% CI, 0.32%-1.0%) for AA patients and 0.25% (95% CI, 0.12%-0.53%) for WA patients. Among the 66 AA patients who developed subsequent invasive breast cancer, 16 (24.2%) developed TNBC compared with 7 (7.4%) of the 94 WA patients who developed subsequent invasive breast cancers and had complete biomarker data (P = .01). CONCLUSIONS AND RELEVANCE: This study is the largest analysis to date of TNBC in the context of racial/ethnic identity and BBD as risk factors. The study found that AA identity persisted as a significant risk factor for TNBC. This finding suggests that AA identity is associated with inherent susceptibility for TNBC pathogenetic pathways.

The predictive value of increased sentinel lymph node volume in breast cancer.

BACKGROUND: Breast cancer sentinel lymph nodes (SLNs) with metastases (mets) are often palpably enlarged. We hypothesized that the volume of the SLN and the size of mets are directly related. SLNs harboring mets are often firm, with increased intra-nodal pressure (INP), and we hypothesized that SLN volume, as well as INP, would correlate directly with SLN metastasis size. METHODS: The SLN volume, INP and met size were measured in 296 SLNs and compared using linear regression analysis. The SLNs were subsequently grouped based upon pN stage. SLN INP and volume were compared between these resultant groups. RESULTS: Increased SLN volume significantly predicted increased SLN met size on univariate and multivariate analysis (p = 0.001 and p = 0.011, respectively). SLN met size predicted increased SLN INP on both univariate and multivariate analysis (both p = 0.001). SLN volume only significantly correlated with increased SLN INP on univariate analysis (p = 0.001). On subgroup analysis of nodal disease, pN1/2/3 nodes (SLN met sizes >2 mm) were significantly larger (p = 0.039 and p = 0.003, respectively) than pN0 and pN1(mi) nodes, and had significantly increased INP (all p = 0.001) as compared to pN0, pN0(i+), and pN1(mi) nodes. CONCLUSIONS: SLN volume and INP increased with increasing SLN met size. The threshold met size for this increase was >2 mm (pN1 disease).

Comparative Analysis of Breast Cancer Phenotypes in African American, White American, and West Versus East African patients: Correlation Between African Ancestry and Triple-Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is more common among African American (AA) and western sub-Saharan African breast cancer (BC) patients compared with White/Caucasian Americans (WA) and Europeans. Little is known about TNBC in east Africa. METHODS: Invasive BC diagnosed 1998-2014 were evaluated: WA and AA patients from the Henry Ford Health System in Detroit, Michigan; Ghanaian/west Africans from the Komfo Anokye Teaching Hospital in Kumasi, Ghana; and Ethiopian/east Africans from the St. Paul's Hospital Millennium Medical College in Addis Ababa, Ethiopia. Histopathology and immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), and HER2/neu expression was performed in Michigan on formalin-fixed, paraffin-embedded samples from all cases. RESULTS: A total of 234 Ghanaian (mean age 49 years), 94 Ethiopian (mean age 43 years), 272 AA (mean age 60 years), and 321 WA (mean age 62 years; p = 0.001) patients were compared. ER-negative and TNBC were more common among Ghanaian and AA compared with WA and Ethiopian cases (frequency ER-negativity 71.1 and 37.1 % vs. 19.8 and 28.6 % respectively, p < 0.0001; frequency TNBC 53.2 and 29.8 % vs. 15.5 and 15.0 %, respectively, p < 0.0001). Among patients younger than 50 years, prevalence of TNBC remained highest among Ghanaians (50.8 %) and AA (34.3 %) compared with WA and Ethiopians (approximately 16 % in each; p = 0.0002). CONCLUSIONS: This study confirms an association between TNBC and West African ancestry; TNBC frequency among AA patients is intermediate between WA and Ghanaian/West Africans consistent with genetic admixture following the west Africa-based trans-Atlantic slave trade. TNBC frequency was low among Ethiopians/East Africans; this may reflect less shared ancestry between AA and Ethiopians.

A prospective cohort study of early discontinuation of adjuvant chemotherapy in women with breast cancer: the breast cancer quality of care study (BQUAL).

For many women with non-metastatic breast cancer, adjuvant chemotherapy prevents recurrence and extends survival. Women who discontinue chemotherapy early may reduce those benefits, but little is known about what predicts early discontinuation. We sought to determine prospectively the rate and reasons for early discontinuation of adjuvant chemotherapy in women with breast cancer. We conducted a prospective cohort study among three U.S. health care organizations. Of 1158 women with newly diagnosed non-metastatic breast cancer, 2006-2010, we analyzed 445 (38.4 %) patients who initiated standard adjuvant chemotherapy as defined by accepted guidelines. We interviewed patients at baseline and twice during treatment regarding sociodemographic/psychosocial factors and treatment decision-making and collected clinical data. They were categorized according to the number of cycles required by the chemotherapy regimen they had initiated. The outcome was early discontinuation (<80 % of planned cycles). Of patients analyzed, 392 (88.1 %) completed the prescribed therapy. The strongest predictor was receipt of a regimen entailing >4 cycles of therapy (18.1 % for longer regimens, 7.4 % for 4 cycles) (odds ratio [OR] 2.59, 95 % CI 1.32-5.08), controlling for race, age, stage, hormone receptor status, social support, optimism, spirituality, stress, and physical symptoms. Higher levels of psychological symptoms on the Memorial symptom assessment scale also increased the odds of early discontinuation (OR 1.92, 95 % CI 0.998-3.68). The large majority of patients who initiated adjuvant chemotherapy for breast cancer completed their prescribed regimens, but early discontinuation was associated with lengthier regimens and, with borderline statistical significance, for those with psychological side effects.