Ex Vivo Infection of Human Skin Models with Herpes Simplex Virus 1: Accessibility of the Receptor Nectin-1 during Formation or Impairment of Epidermal Barriers Is Restricted by Tight Junctions.

Herpes simplex virus 1 (HSV-1) must overcome epidermal barriers to reach its receptors on keratinocytes and initiate infection in human skin. The cell-adhesion molecule nectin-1, which is expressed in human epidermis, acts as an efficient receptor for HSV-1 but is not within reach of the virus upon exposure of human skin under nonpathological conditions. Atopic dermatitis skin, however, can provide an entry portal for HSV-1 emphasizing the role of impaired barrier functions. Here, we explored how epidermal barriers impact HSV-1 invasion in human epidermis and influence the accessibility of nectin-1 for the virus. Using human epidermal equivalents, we observed a correlation of the number of infected cells with tight-junction formation, suggesting that mature tight junctions prior to formation of the stratum corneum prevent viral access to nectin-1. Consequently, impaired epidermal barriers driven by Th2-inflammatory cytokines interleukin 4 (IL-4) and IL-13 as well as the genetic predisposition of nonlesional atopic dermatitis keratinocytes correlated with enhanced infection supporting the impact of functional tight junctions for preventing infection in human epidermis. Comparable to E-cadherin, nectin-1 was distributed throughout the epidermal layers and localized just underneath the tight-junctions. While nectin-1 was evenly distributed on primary human keratinocytes in culture, the receptor was enriched at lateral surfaces of basal and suprabasal cells during differentiation. Nectin-1 showed no major redistribution in the thickened atopic dermatitis and IL-4/IL-13-treated human epidermis in which HSV-1 can invade. However, nectin-1 localization toward tight junction components changed, suggesting that defective tight-junction barriers make nectin-1 accessible for HSV-1 which enables facilitated viral penetration. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a widely distributed human pathogen which productively infects epithelia. The open question is which barriers of the highly protected epithelia must the virus overcome to reach its receptor nectin-1. Here, we used human epidermal equivalents to understand how physical barrier formation and nectin-1 distribution contribute to successful viral invasion. Inflammation-induced barrier defects led to facilitated viral penetration strengthening the role of functional tight-junctions in hindering viral access to nectin-1 that is localized just underneath tight junctions and distributed throughout all layers. We also found nectin-1 ubiquitously localized in the epidermis of atopic dermatitis and IL-4/IL-13-treated human skin implying that impaired tight-junctions in combination with a defective cornified layer allow the accessibility of nectin-1 to HSV-1. Our results support that successful invasion of HSV-1 in human skin relies on defective epidermal barriers, which not only include a dysfunctional cornified layer but also depend on impaired tight junctions.

Minimally Invasive Breast Biopsy After Neoadjuvant Systemic Treatment to Identify Breast Cancer Patients with Residual Disease for Extended Neoadjuvant Treatment: A New Concept.

BACKGROUND: Breast cancer patients with residual disease after neoadjuvant systemic treatment (NAST) have a worse prognosis compared with those achieving a pathologic complete response (pCR). Earlier identification of these patients might allow timely, extended neoadjuvant treatment strategies. We explored the feasibility of a vacuum-assisted biopsy (VAB) after NAST to identify patients with residual disease (ypT+ or ypN+) prior to surgery. METHODS: We used data from a multicenter trial, collected at 21 study sites (NCT02948764). The trial included women with cT1-3, cN0/+ breast cancer undergoing routine post-neoadjuvant imaging (ultrasound, MRI, mammography) and VAB prior to surgery. We compared the findings of VAB and routine imaging with the histopathologic evaluation of the surgical specimen. RESULTS: Of 398 patients, 34 patients with missing ypN status and 127 patients with luminal tumors were excluded. Among the remaining 237 patients, tumor cells in the VAB indicated a surgical non-pCR in all patients (73/73, positive predictive value [PPV] 100%), whereas PPV of routine imaging after NAST was 56.0% (75/134). Sensitivity of the VAB was 72.3% (73/101), and 74.3% for sensitivity of imaging (75/101). CONCLUSION: Residual cancer found in a VAB specimen after NAST always corresponds to non-pCR. Residual cancer assumed on routine imaging after NAST corresponds to actual residual cancer in about half of patients. Response assessment by VAB is not safe for the exclusion of residual cancer. Response assessment by biopsies after NAST may allow studying the new concept of extended neoadjuvant treatment for patients with residual disease in future trials.

Herpes Simplex Virus 1 Can Bypass Impaired Epidermal Barriers upon Ex Vivo Infection of Skin from Atopic Dermatitis Patients.

To infect its human host, herpes simplex virus 1 (HSV-1) must overcome the protective barriers of skin and mucosa. Here, we addressed whether pathological skin conditions can facilitate viral entry via the skin surface and used ex vivo infection studies to explore viral invasion in atopic dermatitis (AD) skin characterized by disturbed barrier functions. Our focus was on the visualization of the onset of infection in single cells to determine the primary entry portals in the epidermis. After ex vivo infection of lesional AD skin, we observed infected cells in suprabasal layers indicating successful invasion in the epidermis via the skin surface which was never detected in control skin where only sample edges allowed viral access. The redistribution of filaggrin, loricrin, and tight-junction components in the lesional skin samples suggested multiple defective mechanical barriers. To dissect the parameters that contribute to HSV-1 invasion, we induced an AD-like phenotype by adding the Th2 cytokines interleukin 4 (IL-4) and IL-13 to healthy human skin samples. Strikingly, we detected infected cells in the epidermis, implying that the IL-4/IL-13-driven inflammation is sufficient to induce modifications allowing HSV-1 to penetrate the skin surface. In summary, not only did lesional AD skin facilitate HSV-1 penetration but IL-4/IL-13 responses alone allowed virus invasion. Our results suggest that the defective epidermal barriers of AD skin and the inflammation-induced altered barriers in healthy skin can make receptors accessible for HSV-1. IMPORTANCE Herpes simplex virus 1 (HSV-1) can target skin to establish primary infection in the epithelium. While the human skin provides effective barriers against viral invasion under healthy conditions, a prominent example of successful invasion is the disseminated HSV-1 infection in the skin of atopic dermatitis (AD) patients. AD is characterized by impaired epidermal barrier functions, chronic inflammation, and dysbiosis of skin microbiota. We addressed the initial invasion process of HSV-1 in atopic dermatitis skin to understand whether the physical barrier functions are sufficiently disturbed to allow the virus to invade skin and reach its receptors on skin cells. Our results demonstrate that HSV-1 can indeed penetrate and initiate infection in atopic dermatitis skin. Since treatment of skin with IL-4 and IL-13 already resulted in successful invasion, we assume that inflammation-induced barrier defects play an important role for the facilitated access of HSV-1 to its target cells.

Diagnosing Pathologic Complete Response in the Breast After Neoadjuvant Systemic Treatment of Breast Cancer Patients by Minimal Invasive Biopsy: Oral Presentation at the San Antonio Breast Cancer Symposium on Friday, December 13, 2019, Program Number GS5-03.

OBJECTIVE: We evaluated the ability of minimally invasive, image-guided vacuum-assisted biopsy (VAB) to reliably diagnose a pathologic complete response in the breast (pCR-B). SUMMARY BACKGROUND DATA: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in up to 80% of women with breast cancer. In such cases, breast surgery, the gold standard for confirming pCR-B, may be considered overtreatment. METHODS: This multicenter, prospective trial enrolled 452 women presenting with initial stage 1-3 breast cancer of all biological subtypes. Fifty-four women dropped out; 398 were included in the full analysis. All participants had an imaging-confirmed partial or complete response to NST and underwent study-specific image-guided VAB before guideline-adherent breast surgery. The primary endpoint was the false-negative rate (FNR) of VAB-confirmed pCR-B. RESULTS: Image-guided VAB alone did not detect surgically confirmed residual tumor in 37 of 208 women [FNR, 17.8%; 95% confidence interval (CI), 12.8-23.7%]. Of these 37 women, 12 (32.4%) had residual DCIS only, 20 (54.1%) had minimal residual tumor (<5 mm), and 19 of 25 (76.0%) exhibited invasive cancer cellularity of ≤10%. In 19 of the 37 cases (51.4%), the false-negative result was potentially avoidable. Exploratory analysis showed that performing VAB with the largest needle by volume (7-gauge) resulted in no false-negative results and that combining imaging and image-guided VAB into a single diagnostic test lowered the FNR to 6.2% (95% CI, 3.4%-10.5%). CONCLUSIONS: Image-guided VAB missed residual disease more often than expected. Refinements in procedure and patient selection seem possible and necessary before omitting breast surgery.

Ex Vivo Infection of Human Skin with Herpes Simplex Virus 1 Reveals Mechanical Wounds as Insufficient Entry Portals via the Skin Surface.

Herpes simplex virus 1 (HSV-1) enters its human host via the skin and mucosa. The open question is how the virus invades this highly protective tissue in vivo to approach its receptors in the epidermis and initiate infection. Here, we performed ex vivo infection studies in human skin to investigate how susceptible the epidermis and dermis are to HSV-1 and whether wounding facilitates viral invasion. Upon ex vivo infection of complete skin, only sample edges with integrity loss demonstrated infected cells. After removal of the dermis, HSV-1 efficiently invaded the basal layer of the epidermis and, from there, gained access to suprabasal layers. This finding supports a high susceptibility of all epidermal layers which correlated with the surface expression of the receptors nectin-1 and herpesvirus entry mediator (HVEM). In contrast, only single infected cells were detected in the separated dermis, where minor expression of the receptors was found. Interestingly, after wounding, nearly no infection of the epidermis was observed via the skin surface. However, if the wounding of the skin samples led to breaks through the dermis, HSV-1 infected mainly keratinocytes via the damaged dermal layer. The application of latex beads revealed only occasional entry via the wounded dermis; however, it facilitated penetration via the wounded skin surface. Thus, we suggest that although the wounded human skin surface allows particle penetration, the skin still provides barriers that prevent HSV-1 from reaching its receptors. IMPORTANCE The human pathogen herpes simplex virus 1 (HSV-1) invades its host via the skin and mucosa, which leads to primary infection of the epithelium. As the various epithelial barriers effectively protect the tissue against viral invasion, successful infection most likely depends on tissue damage. We addressed the initial invasion process in human skin by ex vivo infection to understand how HSV-1 overcomes physical skin barriers and reaches its receptors to enter skin cells. Our results demonstrate that intact skin samples allow viral access only from the edges, while the epidermis is highly susceptible once the basal epidermal layer serves as an initial entry portal. Surprisingly, mechanical wounding did not facilitate HSV-1 entry via the skin surface, although latex beads still penetrated via the lesions. Our results imply that successful invasion of HSV-1 depends on how well the virus can reach its receptors, which was not accomplished by skin lesions under ex vivo conditions.

Correlation analysis of resected breast tissue and implant volume after mastectomy and its association with breast density.

BACKGROUND: The current methods for calculating the ideal implant volume for breast reconstruction are based on pre- or intraoperative volume measurements of the existing breast volume and do not take into account the individual breast density of the woman. This study aims is to identify objective parameters that can help to improve the optimal implant selection. MATERIALS AND METHODS: This retrospective analysis includes 198 breast cancer patients who underwent mastectomy. Breast densities (ACR) measured in mammography and MRI were compared with the removed breast tissue weight and volume of the implants used. In addition, the resected weight was compared directly with the implant volume to calculate a mathematical function. RESULTS: There was no significant correlation between the ACR values and the resected weights [correlation coefficient: mammography:- 0.117 (p = 0.176), MRI - 0.033 (p = 0.756)]. A negative correlation between the implant volumes and both imaging methods could be demonstrated [correlation coefficient: mammography - 0.268; p = 0.002; MRI was - 0.200 (p = 0.055)]. A highly significant correlation between the resected weights and the implant volumes (correlation coefficient 0.744; p < 0.001) was observed. This correlation corresponds to a power function (y = 34.71 x0.39), in which any resected weight can be used for the variable x to calculate the implant volume. CONCLUSION: We were able to show that there is a significant correlation between the resected breast tissue and the implant volume. With our novel potency function, the appropriate implant volume can be calculated for any resected weight making it easier for the surgeon to choose a fitting implant in a simple and more objective manner.

Platelet-rich plasma (PRP) in oncological patients: long-term oncological outcome analysis of the treatment of subcutaneous venous access device scars in 89 breast cancer patients.

PURPOSE: Platelet-rich plasma (PRP) is widely used product, and meta-analyses showed this product to be beneficial when applied to a wound area. This study group has already demonstrated increased patient satisfaction and lower complication rates in breast cancer patients who received PRP after removal of their subcutaneous venous access device. This work is a follow-up analysis focusing on oncologic safety. Currently, there is no long-term data on the use of PRP products in cancer patients available yet. METHODS: Between the years 2012-2016, venous access device removal was supported with the application of Arthrex ACP® (Autologous Conditioned Plasma)-a PRP product to improve the wound-healing process. All surgeries were performed in the breast cancer center of the municipal hospital of Cologne, Holweide, Germany. 35 patients received an application of Arthrex ACP® after port removal compared to the control group of 54 patients. Endpoints were local recurrence-free, distant recurrence-free as well as overall survival. RESULTS: Median follow-up was 45 months. No (0) adverse events were shown for cancer recurrence within the subcutaneous venous access device scar area. Thus, there seems to be no local oncogenic potential of the PRP product. All other endpoints as well as any-cause death numerically favor PRP use. CONCLUSION: PRP products such as Arthrex ACP® seem to be oncological inert when applied after removal of subcutaneous access devices. This is the first study providing long-term data about overall survival, distant recurrence-free and local recurrence-free survival after applying PRP in high-risk cancer patients.

A biomechanical analysis of different meshes for reconstructions of the pelvic floor in the porcine model.

PURPOSE: Many different surgical approaches have been established for the repair of a pelvic organ prolapse. Especially in laparoscopic surgery, it is important to generate easy surgical techniques with similar stability. This study shall simplify the choice of mesh by evaluating three polypropylene meshes regarding their biomechanical properties. METHODS: Biomechanical testing was performed in the porcine model. The meshes are fixated on porcine fresh cadaver cervices after subtotal hysterectomy. The apical part of the mesh is fixated with parallel screw clamps at the testing frame. Forty-one trials were performed overall, subdivided into four subgroups. The groups differ in mesh type and fixation method. Maximum load, displacement at failure and stiffness parameters were evaluated with an Instron 5565® test frame. RESULTS: SERATEX® E11 PA (E11) showed the highest values for maximum load (199 ± 29N), failure displacement (71 ± 12 mm) and stiffness (3.93 ± 0.59 N/mm). There was no significant difference in all three evaluated parameters between SERATEX® B3 PA (B3) and SERATEX® SlimSling® with bilateral fixation (SSB). SERATEX® SlimSling® with unilateral fixation (SSU) had the lowest stiffness (0.91 ± 0.19 N/mm) and maximum load (30 ± 2 N) but no significant difference in displacement at failure. CONCLUSION: All meshes achieved a good tensile strength, but the results of maximum load show that the E11 is superior to the other meshes. Through a bilateral fixation of SERATEX® SlimSling®, a simple operating method is generated without a loss of stability.

Tacks vs. sutures: a biomechanical analysis of sacral bony fixation methods for laparoscopic apical fixations in the porcine model.

PURPOSE: There is a novel surgical procedure, called cervicosacropexy (CESA) and vaginosacropexy (VASA) to treat pelvic organ prolapse and a concomitant urgency and mixed urinary incontinence. As there is little experience with the tapes so far and literature is scanty, the aim of this study was to investigate biomechanical properties for the fixation of the PVDF-tapes with three different fixation methods in context of apical fixations. METHODS: Evaluation was performed on porcine, fresh cadaver sacral spines. A total of 40 trials, divided into 4 subgroups, was performed on the anterior longitudinal ligament. Recorded biomechanical properties were displacement at failure, maximum load and stiffness in terms of the primary endpoints. The failure mode was a secondary endpoint. Group 4 was a reference group to compare single sutures on porcine tissue with those on human tissue. Biomechanical parameters for single sutures on the human anterior longitudinal ligament were evaluated in a previous work by Hachenberg et al. RESULTS: The maximum load for group 1 (two single sutures) was 65 ± 12 N, for group 2 (three titanium tacks arranged in a row) it was 25 ± 10 N and for group 3 (three titanium tacks arranged in a triangle) it was 38 ± 12 N. There was a significant difference between all three groups. The most common failure mode was a "mesh failure" in 9/10 trials for groups 1-3. CONCLUSION: The PVDF-tape fixation with two single sutures endures 2.6 times more load than titanium tacks arranged in a row and 1.7 times more load than titanium tacks arranged in a triangle. The presacral fixation with titanium tacks reduced surgical time compared to the fixation with sutures, nevertheless sutures represent the significantly stronger and cheaper fixation method.

Intraoperative central nipple biopsy in nipple-sparing mastectomy- A retrospective analysis of 211 patients.

Subcutaneous nipple sparing mastectomies (NSM) are an important tool in modern oncoplastic surgery. Especially when an immediate implant-based reconstruction (IBR) is desired, clean margins are of the utmost importance. Central nipple biopsies during surgery serve two main purposes. Most importantly, it is hypothesized that intraoperative pathological evaluation of this biopsy may increase clean margin resection rates. In addition, a general recurrence risk reduction may occur due to the elimination of glandular and ductal components within the nipple. This analysis is a single center, multi-surgeon, retrospective, head to head analysis. Starting in March 2015, intraoperative central nipple biopsy in NSMs with IBR was introduced at the Municipal Breast Cancer Centre Cologne, Holweide, Germany. This trial retrospectively evaluates global complication rates, clean margin status and local recurrence rates for cohort 1 (NSM/no nipple biopsy, n = 103) vs. cohort 2 (NSM with nipple biopsy, n = 108) Median follow-up was 15 months. All implant-based reconstruction procedures used an epipectoral implant pocket. Cohorts were comparable. Global complication rates slightly favored the nipple biopsy cohort with respects to implant loss rate. An involved central nipple biopsy was found in 4.6% (n = 5/108) of the performed NSM procedures leading to the immediate removal of the nipple areola complex. All positive retro-areolar biopsies correlated with a positive nipple biopsy. However, in n = 1 case we found DCIS discontinual proliferation with an involved nipple biopsy, without a correlating positive retro-areolar biopsy (ie, 1 false-negative case was prevented). For the 15 month follow-up, there was no case of local recurrence within nipple areola complex for both cohorts. With this retrospective head to head analysis of 211 patients, it was shown that the central nipple biopsy correlates well with the retro-areolar biopsy. There may be a reduction in false negative rates. The procedure is safe to use and should be offered to NSM patients.

Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)-a translational analysis of the prospective WSG PlanB trial.

BACKGROUND: The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies. METHODS: The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm. RESULTS: Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories. CONCLUSION: Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.

Differential impact of prognostic parameters in hormone receptor-positive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial). METHODS: BCs were centrally reviewed and classified as lobular (n = 353; 14%) or nonlobular (n = 2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models. RESULTS: Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P < .001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P = .673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68). CONCLUSIONS: Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making.

Preexisting musculoskeletal burden and its development under letrozole treatment in early breast cancer patients.

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.

Correction to: Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.

The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated. The original article has been corrected.

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer.

PURPOSE: Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients. METHODS: The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test. RESULTS: In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively). CONCLUSIONS: This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.

The impact of EndoPredict ® on decision making with increasing oncological work experience: can overtreatment be avoided?

BACKGROUND: Estimating distant recurrence risk in women with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer is still challenging. EndoPredict® is a gene expression-based test predicting the likelihood of recurrent disease. We analyzed the difference in oncological decision making with and without the knowledge of gene expression tests. PATIENTS AND METHODS: This is a retrospective analysis including patients diagnosed with hormone-receptor positive, Her2 negative breast cancer between 2011 and 2015 at the Municipal Breast Cancer Centre Cologne, Germany. All patients received an evaluation by EndoPredict®. An oncological tumor board (TB) with knowledge of these results served as a baseline (control group). This baseline was compared to the treatment decision (adjuvant chemotherapy yes vs. no) made by oncologists with different experience levels (less than 5 years, between 5 and 15 years, and more than 15 years) who were not provided the EndoPredict® scores. All clinicians had access to clinical as well to histopathological data. RESULTS: There was no significant difference between control group and the oncologists with different experience levels concerning a chemotherapy indication. A trend could be shown in the subgroup of nodal negative patients between the treatment recommendation and physicians with more than 15 years of experience (p = 0.088). A further trend could be demonstrated in the subgroup of patients with a low Ki67 index (≤ 14%) (p = 0.063) between physician with 5-10 years of clinical experience and official treatment recommendation. CONCLUSION: It seems that inexperienced physicians may profit from the use of EndoPredict® to avoid an overtreatment. In nodal negative patients and patients with a low Ki67 index, undertreatment can be avoided with the use of EndoPredict® (borderline significance). Further prospective studies with larger study cohorts are needed to further validate this tool.

Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.

BACKGROUND: The prospective phase 3 PlanB trial used the Oncotype DX® Recurrence Score® (RS) to define a genomically low-risk subset of clinically high-risk pN0-1 early breast cancer (EBC) patients for treatment with adjuvant endocrine therapy (ET) alone. Here, we report five-year data evaluating the prognostic value of RS, Ki-67, and other traditional clinicopathological parameters. METHODS: A central tumour bank was prospectively established within PlanB. Following an early amendment, hormone receptor (HR)+ , pN0-1 RS ≤ 11 patients were recommended to omit chemotherapy. Patients with RS ≥ 12, pN2-3, or HR-negative/HER2-negative disease were randomised to anthracycline-containing or anthracycline-free chemotherapy. Primary endpoint: disease-free survival (DFS). PlanB Clinicaltrials.gov identifier: NCT01049425. FINDINGS: From 2009 to 2011, PlanB enrolled 3198 patients (central tumour bank, n = 3073) with the median age of 56 years, 41.1% pN+, and 32.5% grade 3 EBC. Chemotherapy was omitted in 348/404 (86.1%) eligible RS ≤ 11 patients. After 55 months of median follow-up, five-year DFS in ET-treated RS ≤ 11 patients was 94% (in both pN0 and pN1) versus 94% (RS 12-25) and 84% (RS > 25) in chemotherapy-treated patients (p < 0.001); five-year overall survival (OS) was 99 versus 97% and 93%, respectively (p < 0.001). Nodal status, central/local grade, tumour size, continuous Ki-67, progesterone receptor (PR), IHC4, and RS were univariate prognostic factors for DFS. In a multivariate analysis including all univariate prognostic markers, only pN2-3, central and local grade 3, tumour size >2 cm, and RS, but not IHC4 or Ki-67 were independent adverse factors. If RS was excluded, IHC4 or both Ki-67 and PR entered the model. The impact of RS was particularly pronounced in patients with intermediate Ki-67 (>10%, <40%) tumours. INTERPRETATION: The excellent five-year outcomes in clinically high-risk, genomically low-risk (RS ≤ 11) pN0-1 patients without adjuvant chemotherapy support using RS with standardised pathology for treatment decisions in HR+ HER2-negative EBC. Ki-67 has the potential to support patient selection for genomic testing.

A Retrospective Multicenter Analysis of Diagon/Gel® 4Two Implant in 209 Cases of Reconstructive Breast Surgery.

BACKGROUND/AIM: Breast cancer was the most common cancer in women in 2020. Breast reconstruction is an elementary component of modern breast surgery. This is especially important after oncological treatments. This is a retrospective multicenter study comparing Diagon\Gel® 4Two implants with different implants chosen by the treating surgeon. Diagon\Gel® 4Two (Polytech Health & Aesthetics, Germany) are anatomical silicone implants. PATIENTS AND METHODS: A total of 209 patients underwent surgery. All patients were treated in the period from 2001 to 2019. All procedures were subcutaneous mastectomies. The surgical techniques used were either skin-sparing mastectomies or nipple-sparing mastectomies. Surgery was performed with Diagon/Gel® 4Two implant or treatment of choice implant by the treating physician. Endpoints were major and minor complication rates. The average follow-up time was 5 years. In total, 110 subjects were asked about their satisfaction with the treatment. RESULTS: A total of 155 procedures were performed in the Diagon/Gel® 4Two implant group. One hundred and sixty procedures were done in the comparison group. Concerning either minor or major complications, there were no significant differences between both groups. The postoperative patient survey showed high satisfaction scores for both. There was significantly higher patient satisfaction among the study participants in the Diagon/Gel® 4Two implant group compared to the comparison group (p<0.01). CONCLUSION: The Diagon/Gel® 4Two implants are safe alternatives in direct comparison to previously used breast implants. Our study even demonstrated a slight superiority concerning patient satisfaction. Based on this study, further implants can be compared concerning both the direct perioperative complication rate and patient satisfaction.

Evaluation of the Impact of Adaptive Progressive Supervised Resistance Training on Strength and Quality of Life in Patients with Breast Cancer during Chemotherapy: The VALESCO Study.

INTRODUCTION: Breast cancer patients (BCP) experience considerable side effects during and after treatment. Several studies have shown positive effects of exercise on therapy-related side-effects such as loss of muscle strength, loss of bone mineral density, lymphedema, and several elements of quality of life (QoL). Resistance exercise has proven effective and beneficial for BCP; however, optimal individual training parameters remain to be determined. METHODS: The aim of our study was to implement an adaptive, progressive, supervised resistance protocol for BCPs during chemotherapy, improving muscle strength, physical condition, and overall QoL while reducing therapy-induced side-effects. Forty patients receiving adjuvant chemotherapy were included 6-12 weeks post-OP. Twenty patients underwent high intensity resistance-training twice a week for 12 weeks, and the control group received usual care. RESULTS: Strength parameters improved significantly in the intervention group and in different scales of QoL. We documented a cyclic performance level dependent on the number of days after treatment. CONCLUSION: Adaptive resistance training with simple training control mechanisms proved to be effective regarding optimal intensity in each training session and needs to be implemented in further studies in order to guarantee adequate loads in accordance to the training protocols.