Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

Learning how to perform ultrasound-guided interventions with and without augmented reality visualization: a randomized study.

OBJECTIVES: Augmented reality (AR), which entails overlay of in situ images onto the anatomy, may be a promising technique for assisting image-guided interventions. The purpose of this study was to investigate and compare the learning experience and performance of untrained operators in puncture of soft tissue lesions, when using AR ultrasound (AR US) compared with standard US (sUS). METHODS: Forty-four medical students (28 women, 16 men) who had completed a basic US course, but had no experience with AR US, were asked to perform US-guided biopsies with both sUS and AR US, with a randomized selection of the initial modality. The experimental setup aimed to simulate biopsies of superficial soft tissue lesions, such as for example breast masses in clinical practice, by use of a turkey breast containing olives. Time to puncture(s) and success (yes/no) of the biopsies was documented. All participants completed questionnaires about their coordinative skills and their experience during the training. RESULTS: Despite having no experience with the AR technique, time to puncture did not differ significantly between AR US and sUS (median [range]: 17.0 s [6-60] and 14.5 s [5-41], p = 0.16), nor were there any gender-related differences (p = 0.22 and p = 0.50). AR US was considered by 79.5% of the operators to be the more enjoyable means of learning and performing US-guided biopsies. Further, a more favorable learning curve was achieved using AR US. CONCLUSIONS: Students considered AR US to be the preferable and more enjoyable modality for learning how to obtain soft tissue biopsies; however, they did not perform the biopsies faster than when using sUS. KEY POINTS: • Performance of standard and augmented reality US-guided biopsies was comparable • A more favorable learning curve was achieved using augmented reality US. • Augmented reality US was the preferred technique and was considered more enjoyable.

Interobserver variability and likelihood of malignancy for fifth edition BI-RADS MRI descriptors in non-mass breast lesions.

OBJECTIVE: Non-mass enhancement (NME) in breast MRI is the most common feature of ductal carcinoma in situ (DCIS). We sought to evaluate the interobserver variability and positive predictive value (PPV) for malignancy of NME descriptors using the fifth edition BI-RADS lexicon focusing on the newly introduced "clustered ring enhancement" pattern. MATERIALS AND METHODS: Breast MRIs of 129 patients who had undergone MRI-guided vacuum-assisted biopsy (VAB) in our institution were reviewed. Studies assessed as NME were classified according to the fifth edition BI-RADS lexicon by two breast radiologists. Consensus was reached by involving a third radiologist. Interobserver variability and PPV for malignancy were assessed. RESULTS: Seventy-two of 129 studies were assessed as NME. The disagreement rate in the first assessment step (mass vs. NME) was low at 9.3% (ĸ = 0.81, 95% confidence interval [CI] 0.71-0.91). The disagreement rate for distribution patterns was 23.6% (ĸ = 0.67, 95% CI 0.54-0.80) and 22.2% (ĸ = 0.69, 95% CI 0.56-0.81) for internal enhancement patterns. Clustered ring enhancement (PPV 53.85, p = 0.038) and segmental distribution (PPV 62.5%, p = 0.028) had the highest malignancy rates among internal enhancement and distribution patterns with a significant result; the combination of clustered ring enhancement and segmental distribution raised the malignancy rate by approximately 4% (PPV 66.67%, p = 0.049). CONCLUSION: There was a high agreement rate among readers when differentiating NME from mass lesions. The agreement rate was lower when assessing the distribution and internal enhancement pattern descriptors, but still substantial. The descriptors clustered ring enhancement and segmental distribution were significant predictors of malignancy. KEY POINTS: • Non-mass enhancement is a common morphological feature of non-invasive breast cancer (DCIS) in MRI. Differentiation between potentially malignant and benign changes may be very challenging. • Since clustered ring enhancement and segmental distribution are both significant predictors of malignancy, the awareness of this important finding, combined with high-quality image interpretation skills, may improve the tumor detection rate. • The combination of clustered ring enhancement and segmental distribution increases the positive predictive value for malignancy, which may be relevant for clinical practice.

Correction to: Towards clinical grating-interferometry mammography.

The article Towards clinical grating-interferometry mammography, written by Carolina Arboleda, Zhentian Wang, Konstantins Jefimovs, Thomas Koehler, Udo Van Stevendaal, Norbert Kuhn, Bernd David, Sven Prevrhal, Kristina Lång, Serafino Forte, Rahel Antonia Kubik-Huch, Cornelia Leo.

Towards clinical grating-interferometry mammography.

OBJECTIVES: Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, as several research works have demonstrated in a pre-clinical setting, since it is able to provide attenuation, differential phase contrast, and scattering images simultaneously. In order to translate this technique to the clinics, it has to be adapted to cover a large field-of-view within a clinically acceptable exposure time and radiation dose. METHODS: We set up a grating interferometer that fits into a standard mammography system and fulfilled the aforementioned conditions. Here, we present the first mastectomy images acquired with this experimental device. RESULTS AND CONCLUSION: Our system performs at a mean glandular dose of 1.6 mGy for a 5-cm-thick, 18%-dense breast, and a field-of-view of 26 × 21 cm2. It seems to be well-suited as basis for a clinical-environment device. Further, dark-field signals seem to support an improved lesion visualization. Evidently, the effective impact of such indications must be evaluated and quantified within the context of a proper reader study. KEY POINTS: • Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, since it is sensitive to refraction and scattering and thus provides additional tissue information. • The most straightforward way to do grating-interferometry in the clinics is to modify a standard mammography device. • In a first approximation, the doses given with this technique seem to be similar to those of conventional mammography.

Impact of a Surgical Sealing Patch on Lymphatic Drainage After Axillary Dissection for Breast Cancer: The SAKK 23/13 Multicenter Randomized Phase III Trial.

BACKGROUND: Several studies and a meta-analysis showed that fibrin sealant patches reduced lymphatic drainage after various lymphadenectomy procedures. Our goal was to investigate the impact of these patches on drainage after axillary dissection for breast cancer. METHODS: In a phase III superiority trial, we randomized patients undergoing breast-conserving surgery at 14 Swiss sites to receive versus not receive three large TachoSil® patches in the dissected axilla. Axillary drains were inserted in all patients. Patients and investigators assessing outcomes were blinded to group assignment. The primary endpoint was total volume of drainage. RESULTS: Between March 2015 and December 2016, 142 patients were randomized (72 with TachoSil® and 70 without). Mean total volume of drainage in the control group was 703 ml [95% confidence interval (CI) 512-895 ml]. Application of TachoSil® did not significantly reduce the total volume of axillary drainage [mean difference (MD) -110 ml, 95% CI -316 to 94, p = 0.30]. A total of eight secondary endpoints related to drainage, morbidity, and quality of life were not improved by use of TachoSil®. The mean total cost per patient did not differ significantly between the groups [34,253 Swiss Francs (95% CI 32,625-35,880) with TachoSil® and 33,365 Swiss Francs (95% CI 31,771-34,961) without, p = 0.584]. In the TachoSil® group, length of stay was longer (MD 1 day, 95% CI 0.3-1.7, p = 0.009), and improvement of pain was faster, although the latter difference was not significant [2 days (95% CI 1-4) vs. 5.5 days (95% CI 2-11); p = 0.2]. CONCLUSIONS: TachoSil® reduced drainage after axillary dissection for breast cancer neither significantly nor relevantly.

Overexpression of Lox in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancers. It is associated with a poor prognosis and typically earlier onset of metastasis in comparison with other breast cancer subtypes. Since TNBC lacks the expression of estrogen and progesterone receptors and Her2 status is also negative, there is currently no target that can be used for systemic therapy. Epithelial-mesenchymal transition (EMT) plays an important role in tumor progression and metastasis. In this study, we examined a subset of EMT markers consisting of Snail, Twist-1 and Lox in TNBC and non-TNBC breast cancer subtypes and analyzed their expression pattern in regard to subtype, clinico-pathological parameters and prognosis. EXPERIMENTAL DESIGN: We analyzed 659 breast cancer samples from two tissue microarrays. Breast cancer samples were categorized into two groups according to hormone receptor expression and Her2 status (n = 146 were triple negative, n = 513 were non triple-negative). Immunohistochemical expression of Snail, Twist-1 and Lox was semi-quantitatively analyzed using a three-tiered (weak-moderate-strong) scoring system. Results were statistically analyzed and correlated to clinico-pathological parameters and overall survival. RESULTS: Strong overexpression of Lox was significantly higher in triple negative breast cancers when compared to non triple-negative breast cancers (p < 0.001). No difference was seen between the groups regarding Snail and Twist expression (p > 0.05). In addition, Lox expression was significantly stronger in poorly differentiated (G3) breast cancers (p < 0.001 for Lox). CONCLUSIONS: The EMT marker Lox has a differential expression pattern in breast cancer, being significantly overexpressed in triple negative breast cancers. We could not link this expression to prognosis, however, this marker might be explored in future studies as possible target for systemic therapy of TNBC.

Breast cancer screening attendance in two Swiss regions dominated by opportunistic or organized screening.

BACKGROUND: In Switzerland, the French-speaking region has an organized breast cancer (BC) screening program; in the German-speaking region, only opportunistic screening until recently had been offered. We evaluated factors associated with attendance to breast cancer screening in these two regions. METHODS: We analyzed the data of 50-69 year-old women (n = 2769) from the Swiss Health Survey 2012. Factors of interest included education level, place of residence, nationality, marital status, smoking history, alcohol consumption, physical activity, diet, self-perceived health, history of chronic diseases and mental distress, visits to medical doctors and cervical and colorectal cancer screening. Outcome measures were dichotomized into ≤2 years since most recent mammography versus >2 years or never. RESULTS: In the German- and French-speaking regions, mammography attendance within the last two years was 34.9 % and 77.8 %, respectively. In the French region, moderate alcohol consumption (adjusted OR 2.01, 95 % CI 1.28-3.15) increased screening attendance. Compared to those with no visit to a physician during the recent year, women in both regions with such visits attended statistically significantly more often BC screening (1-5 times vs. no visit: German (adjusted OR 3.96, 95 % CI 2.58-6.09); French: OR 7.25, 95 % CI 4.04-13.01). Non-attendance to cervical screening had a negative effect in both the German (adjusted OR 0.44, 95 % CI 0.25-0.79) and the French region (adjusted OR 0.57, 95 % CI 0.35-0.91). The same was true for colorectal cancer screening (German (adjusted OR 0.66, 95 % CI 0.52-0.84); French: OR 0.52, 95 % CI 0.33-0.83). No other factor was associated with BC screening and none of the tests of interaction comparing the two regions revealed statistically significant results. CONCLUSION: The effect of socio-demographic characteristics, lifestyle, health factors and screening behavior other than mammography on non-attendance to BC screening did not differ between the two regions with mainly opportunistic and organized screening, respectively, and did not explain the large differences in attendance between regions. Other potential explanations such as public promotion of attendance for BC screening, physicians' recommendations regarding mammography participation or women's beliefs should be further investigated.

Differential expression of epithelial­mesenchymal transition and stem cell markers in intrinsic subtypes of breast cancer.

The transcription factors SLUG and SOX9 have been shown to define mammary stem cell state. Similarly, epithelial­mesenchymal transition (EMT) markers (E-Cadherin, mTOR) have been shown to play a role in tumor-progression and metastatic potential in breast cancer. Finally, SOX10 is known to be expressed in breast cancer as well. The overexpressions of EMT and stem cell markers have been shown to correlate with poor overall survival. In this study, we examined whether the expression of these markers correlates with intrinsic subtypes of breast cancer and whether there is a prognostic difference in their expression-profile. We analyzed 617 breast cancer samples from two tissue micro arrays. Breast cancer samples were categorized into three groups according to hormone receptor expression and HER2-status as Luminal A/B, HER2-positive, and triple negative subgroup. Immunohistochemical expressions of SLUG, SOX9, SOX10, E-Cadherin, and mTOR were semi-quantitatively analyzed using a two-tiered and three-tiered scoring system in which cytoplasmic and nuclear stains were considered. Strong nuclear expression of SLUG was observed preferentially in triple negative but not in Luminal A/B or HER2-positive cases (24 vs. 3 and 0 %, p < 0.001). Loss of SOX9 in the nuclear stain was less frequent in triple negative than in Luminal A/B or HER2-positive cases (4 vs. 9 vs. 13 %, p < 0.001). Expression of nuclear SOX10 was lower in triple negative than in Luminal A/B and HER2-positive cases (67 vs.78 and 79 %, p = 0.012). E-Cadherin loss was observed only in Luminal A/B tumors (p = 0.016), no difference in the mTOR expression was seen between any of the three groups. No correlation to conventional histopathological-parameters or stage could be established in our cohort. Our study shows an inversed preferential nuclear expression of SLUG, SOX10, and SOX9 in triple negative and non-triple negative cases. This information is important in understanding the biology of triple negative breast cancer, also in terms of future studies dealing with targeted therapies based on the alterations of EMT and stem cell markers.

Quantitative breast MRI: 2D histogram analysis of diffusion tensor parameters in normal tissue.

OBJECT: Diffusion tensor imaging (DTI) of the breast may provide a powerful new approach for the detection of intraductal processes. The aim of this investigation was to characterize the relation between diffusion tensor parameters [fractional anisotropy (FA), mean diffusivity (MD)] in normal breast tissue to obtain information on the microenvironment of the diffusing water molecules and to provide a systematic approach for DTI analysis. MATERIALS AND METHODS: Seven female, healthy volunteers underwent prospective double-spin-echo prepared echo-planar diffusion-weighted sequence (TR/TE 8,250 ms/74 ms, b values 0 and 500 s/mm (2), six encoding directions, 12 averages, 35 slices) in 4 consecutive weeks (3.0 T). Quantitative maps of diffusion tensor parameters were computed offline with custom routines. The interdependence of MD and FA in different voxels was analysed by linear and exponential regression. RESULTS: All MD and FA maps were of excellent quality. A consistent pattern was observed in that lower fractional anisotropy values were more likely associated with higher mean diffusivity values. The dependence exhibited an exponential behavior with a correlation coefficient R = 0.60 (R linear = 0.57). CONCLUSION: The likelihood with which FA and MD values are observed in a voxel within normal breast tissue is characterized by a specific pattern, which can be described by an exponential model. Moreover, we could show that the proposed technique does not depend on the menstrual cycle.

Long-Term Follow-Up of High-Risk Breast Lesions at Vacuum-Assisted Biopsy without Subsequent Surgical Resection.

Introduction: B3-lesions of the breast are a heterogeneous group of neoplasms, associated with a higher risk of breast cancer. Recent studies show a low upgrade rate into malignancy after subsequent open surgical excision (OE) of most B3-lesions when proven by vacuum-assisted biopsy (VAB). However, there is a lack of long-term follow-up data after VAB of high-risk lesions. The primary aim of this study was to demonstrate whether follow-up of B3 lesions is a beneficial and reliable alternative to OE in terms of long-term outcome. The secondary aim was to identify patient and lesion characteristics of B3 lesions for which OE is still necessary. Methods: This retrospective multicenter study was conducted at 8 Swiss breast centers between 2010 and 2019. A total of 278 women (mean age: 53.5 ± 10.7 years) with 286 B3-lesions who had observation only and who had at least 24 months of follow-up were included. Any event during follow-up (ductal carcinoma in situ [DCIS], invasive cancer, new B3-lesion) was systematically recorded. Data from women who had an event during follow-up were compared with those who did not. The results for the different B3 lesions were analyzed using the t test and Fisher's exact test. A p value of <0.05 was considered statistically significant. Results: The median follow-up interval was 59 months (range: 24-143 months) with 52% (148/286) having a follow-up of more than 5 years. During follow-up, in 42 women, 44 suspicious lesions occurred, with 36.4% (16/44) being invasive cancer and 6.8% (3/44) being DCIS. Thus, 6.6% (19/286) of all women developed malignancy during follow-up after a median follow-up interval of 6.5 years (range: 31-119 months). The initial histology of the B3 lesion influenced the subsequent occurrence of a malignant lesion during follow-up (p < 0.038). The highest malignancy-developing rate was observed in atypical ductal hyperplasia (ADH) (24%, 19/79), while all other B3-lesions had malignant findings ipsi- and contralateral between 0% and 6%. The results were not influenced by the VAB method (Mx-, US-, magnetic resonance imaging-guided), the radiological characteristics of the lesion, or the age or menopausal status of the patient (p > 0.12). Conclusion: With a low risk of <6% of developing malignancy, VAB followed by long-term follow-up is a safe alternative to OE for most B3-lesions. A higher malignancy rate only occurred in ADH (24%). Based on our results, radiological follow-up should be bilateral, preferable using the technique of initial diagnosis. As we observed a late peak (6-7 years) of breast malignancies after B3-lesions, follow-up should be continued for a longer period (>10 years). Knowledge of these long-term outcome results will be helpful in making treatment decisions and determining the optimal radiological follow-up interval.

The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer.

BACKGROUND: Several classification systems are available to assess pathological response to neoadjuvant chemotherapy in breast cancer, but reliable biomarkers to predict the efficiency of primary systemic therapy (PST) are still missing. Deregulation of gap junction channel forming connexins (Cx) has been implicated in carcinogenesis and tumour progression through loss of cell cycle control. In this study we correlated Cx expression and cell proliferation with disease survival and pathological response to neoadjuvant chemotherapy in breast cancers using existing classification systems. METHODS: The expression of Cx26, Cx32, Cx43, Cx46 and Ki67 was evaluated in 96 breast cancer patients prior to and after neoadjuvant chemotherapy using duplicate cores in tissue microarrays (TMA). Cx plaques of <1µm were detected with multilayer, multichannel fluorescence digital microscopy. Current classifications to assess residual tumour burden after primary systemic therapy included the EWGBSP, CPS-EG, Miller-Payne, Sataloff and NSABP systems. RESULTS: In our cohort dominated by hormone receptor (ER/PR) positive and HER2 negative cases, only the CPS-EG classification showed prognostic relevance: cases with scores 1-2 had significantly better overall survival (p=0.015) than cases with scores 3-5. Pre-chemotherapy Cx43 expression correlated positively with hormone receptor status both before and after chemotherapy and had a negative correlation with HER2 expression pre-chemotherapy. There was a positive correlation between Cx32 and HER2 expression pre-chemotherapy and between Cx32 and Ki67 expression post-chemotherapy. A negative correlation was found between post-chemotherapy Cx46 and Ki67 expression. Decreased post-chemotherapy Cx26 expression (<5%) statistically correlated with better overall survival (p=0.011). Moderate or higher Cx46 expression (>20%) pre- and post-chemotherapy correlated with significantly better survival in the intermediate prognostic subgroups of EWGBSP TR2b (p(pre-chemo)=0.006; Sataloff TB (p(pre-chemo)=0.005; p(post-chemo)=0.029) and in Miller-Payne G3 (p(pre-chemo)=0.002; p(post-chemo)=0.012) classifications. Pre-chemotherapy, Cx46 expression was the only marker that correlated with overall survival within these subgroups. CONCLUSION: Our results suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy.

Pertuzumab as second­ or later­line therapy for human epidermal growth factor receptor 2­positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy. Physicians from nine major Swiss oncology centers retrospectively completed a questionnaire for each pertuzumab-naive patient who was treated with pertuzumab as a second- or later-line therapy. Of 35 patients with HER2-positive mBC (median age, 49 years; range, 35-87 years), 14 received pertuzumab as a second-line therapy, 6 as a third-line therapy, and 15 as a fourth- or later-line therapy. A total of 20 patients (57%) died during the study period. The median overall survival was 74.2 months (95% confidence interval, 47.6-139.8 months). Grade (G) 3/4 adverse events (AEs) were reported in 14% of patients, with only 1 patient discontinuing therapy due to pertuzumab-related toxicities. The most common AE was fatigue (overall, 46%; G3, 11%). Overall, congestive heart disease occurred in 14% of patients (G3, 6%), nausea in 14% of patients (all G1), and myelosuppression in 12% of patients (G3, 6%). In conclusion, the median overall survival of patients who underwent second- or later-line pertuzumab treatment was similar to that reported for patients who underwent first-line pertuzumab treatment, and the safety profile was acceptable. These data support the use of pertuzumab for second- or later-line therapy when it was not administered as first-line therapy.

Third International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions).

The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH.

Association of Axillary Dissection With Systemic Therapy in Patients With Clinically Node-Positive Breast Cancer.

Importance: The role of axillary lymph node dissection (ALND) to determine nodal burden to inform systemic therapy recommendations in patients with clinically node (cN)-positive breast cancer (BC) is currently unknown. Objective: To address the association of ALND with systemic therapy in cN-positive BC in the upfront surgery setting and after neoadjuvant chemotherapy (NACT). Design, Setting, and Participants: This was a prospective, observational, cohort study conducted from August 2018 to June 2022. This was a preplanned study within the phase 3 randomized clinical OPBC-03/TAXIS trial. Included were patients with confirmed cN-positive BC from 44 private, public, and academic breast centers in 6 European countries. After NACT, residual nodal disease was mandatory, and a minimum follow-up of 2 months was required. Exposures: All patients underwent tailored axillary surgery (TAS) followed by ALND or axillary radiotherapy (ART) according to TAXIS randomization. TAS removed suspicious palpable and sentinel nodes, whereas imaging-guidance was optional. Systemic therapy recommendations were at the discretion of the local investigators. Results: A total of 500 patients (median [IQR] age, 57 [48-69] years; 487 female [97.4%]) were included in the study. In the upfront surgery setting, 296 of 335 patients (88.4%) had hormone receptor (HR)-positive and Erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-negative disease: 145 (49.0%) underwent ART, and 151 (51.0%) underwent ALND. The median (IQR) number of removed positive lymph nodes without ALND was 3 (1-4) nodes compared with 4 (2-9) nodes with ALND. There was no association of ALND with the proportion of patients undergoing adjuvant chemotherapy (81 of 145 [55.9%] vs 91 of 151 [60.3%]; adjusted odds ratio [aOR], 0.72; 95% CI, 0.19-2.67) and type of systemic therapy. Of 151 patients with NACT, 74 (51.0%) underwent ART, and 77 (49.0%) underwent ALND. The ratio of removed to positive nodes was a median (IQR) of 4 (3-7) nodes to 2 (1-3) nodes and 15 (12-19) nodes to 2 (1-5) nodes in the ART and ALND groups, respectively. There was no observed association of ALND with the proportion of patients undergoing postneoadjuvant systemic therapy (57 of 74 [77.0%] vs 55 of 77 [71.4%]; aOR, 0.86; 95% CI, 0.43-1.70), type of postneoadjuvant chemotherapy (eg, capecitabine: 10 of 74 [13.5%] vs 10 of 77 [13.0%]; trastuzumab emtansine-DM1: 9 of 74 [12.2%] vs 11 of 77 [14.3%]), or endocrine therapy (eg, aromatase inhibitors: 41 of 74 [55.4%] vs 36 of 77 [46.8%]; tamoxifen: 8 of 74 [10.8%] vs 6 of 77 [7.8%]). Conclusion: Results of this cohort study suggest that patients without ALND were significantly understaged. However, ALND did not inform systemic therapy recommendations.

The value of endocervical curettage after conization for cervical intraepithelial neoplasia.

The objective of this study is to assess the value of postcone endocervical curettage, after conization of cervical intraepithelial neoplasia or carcinoma as a predictive tool for residual lesions. This is a retrospective observational study. All data were obtained by the University Hospital of Zurich, Department of Gynaecology. One hundred fifty patients underwent hysterectomy within 12 months after conization and endocervical curettage from 1993 to 2006. To analyze the sensitivity, specificity, and the positive predictive value (PPV) and negative predictive value (NPV) of the endocervical curettage after conization, we used the Fisher exact test and χ(2) test. The main outcome measures are the sensitivity and specificity as well as the PPV and NPV of the postconization endocervical curettage. The endocervical curettage exhibited a sensitivity of 0.38, a specificity of 0.85, a PPV of 0.56, and an NPV of 0.73. Comparing patients younger than 50 years to women 50 years or older, endocervical curettage had a sensitivity of 0.35 and 0.44, a specificity of 0.83 and 0.94, a PPV of 0.46 and 0.88, and an NPV of 0.76 and 0.63, respectively. The endocervical curettage after conization of cervical intraepithelial neoplasia does not generally improve the prediction of residual lesions. However, in women 50 years or older, a higher specificity and PPV, 0.94 and 0.88, respectively, was observed. Therefore, this subgroup of patients may benefit from an endocervical curettage.

Tailored axillary surgery in patients with clinically node-positive breast cancer: Pre-planned feasibility substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

AIM: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. METHODS: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. RESULTS: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. CONCLUSIONS: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.

Local spread of cervical cancer revisited: a clinical and pathological pattern analysis.

BACKGROUND: Local tumor spread of cervical cancer is currently considered as radial progressive intra- and extracervical permeation. For radical tumor resection or radiation the inclusion of a wide envelope of tumor-free tissue is demanded. However, this concept may lead to considerable treatment-related morbidity and does not prevent local relapse. We propose an alternative model of local tumor propagation involving permissive compartments related to embryonic development. METHODS: We analyzed local tumor spread macroscopically and microscopically in consecutive patients with advanced cervical cancer and post-irradiation recurrences. RESULTS: Macroscopically, all 33 stage I B (>2cm) tumors, 40 of 42 stage II tumors and 32 of 44 stage III B tumors were confined to the embryologically defined uterovaginal (Müllerian) compartment. Local tumor permeation deformed the uterovaginal compartment mirroring the mesenchyme distribution of the Müllerian anlage at the corresponding pelvic level in cases of symmetrical tumor growth. Tumor transgression into adjacent compartments mainly involved the embryologically related lower urinary tract. Compartmental transgression was associated with larger tumor size, paradox improvement in oxygenation and an increase in microvessel density. Post-irradiation pelvic relapse landscapes were congruent with the inflated Müllerian compartment. Microscopically, all locally advanced primary cancers and post-irradiation recurrences were confined to the uterovaginal and lower urinary tract compartments. CONCLUSION: Cervical cancer spreads locally within the uterovaginal compartment derived from the Müllerian anlage. Compartment transgression is a relatively late event in the natural disease course associated with distinct phenotypic changes of the tumor. Compartmental tumor permeation suggests a new definition of local treatment radicality.

Publisher Correction: Breast cancer drug approvals by the US FDA from 1949 to 2018.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

FDA and EMA Approvals of New Breast Cancer Drugs-A Comparative Regulatory Analysis.

Breast cancer is the most common cancer in women worldwide and the solid tumor type for which the highest number of drugs have been approved to date. This study examines new drug approvals for breast cancer by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), based on an analysis of regulatory documents from both agencies for the period from 1995 to 2018. Of the 29 breast cancer drugs approved over this time span, 17 received positive decisions from both the FDA and EMA, including all drugs licensed after 2008. Nineteen of the 25 FDA-approved drugs, but none of the EMA approvals, benefited from special regulatory pathways (such as fast track, breakthrough therapy, or priority review). In the U.S.A., four accelerated approvals were granted (of which one, for bevacizumab, was later revoked), while only two drugs received provisional approvals following EMA review. New breast cancer drugs were approved approximately twelve months earlier in the United States than in Europe. These results suggest that a broader use of special regulatory pathways by EMA could help to accelerate access to novel drugs for European breast cancer patients.