Real-world use of multigene signatures in early breast cancer: differences to clinical trials.

PURPOSE: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy. METHODS: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0-25, high RS: 26-100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials. RESULTS: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive. CONCLUSIONS: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer patients undergoing mastectomy with one to two metastatic sentinel lymph nodes: sub-analysis of the SINODAR-ONE multicentre randomized clinical trial and reopening of enrolment.

BACKGROUND: The initial results of the SINODAR-ONE randomized clinical trial reported that patients with T1-2 breast cancer and one to two macrometastatic sentinel lymph nodes treated with breast-conserving surgery, sentinel lymph node biopsy only, and adjuvant therapy did not present worse 3-year survival, regional recurrence, or distant recurrence rates compared with those treated with axillary lymph node dissection. To extend the recommendation of axillary lymph node dissection omission even in patients treated with mastectomy, a sub-analysis of the SINODAR-ONE trial is presented here. METHODS: Patients with T1-2 breast cancer and no more than two metastatic sentinel lymph nodes undergoing mastectomy were analysed. After sentinel lymph node biopsy, patients were randomly assigned to receive either axillary lymph node dissection followed by adjuvant treatment (standard arm) or adjuvant treatment alone (experimental arm). The primary endpoint was overall survival. The secondary endpoint was recurrence-free survival. RESULTS: A total of 218 patients were treated with mastectomy; 111 were randomly assigned to the axillary lymph node dissection group and 107 to the sentinel lymph node biopsy-only group. At a median follow-up of 33.0 months, there were three deaths (two deaths in the axillary lymph node dissection group and one death in the sentinel lymph node biopsy-only group). There were five recurrences in each treatment arm. No axillary lymph node recurrence was observed. The 5-year overall survival rates were 97.8 and 98.7 per cent in the axillary lymph node dissection treatment arm and the sentinel lymph node biopsy-only treatment arm, respectively (P = 0.597). The 5-year recurrence-free survival rates were 95.7 and 94.1 per cent in the axillary lymph node dissection treatment arm and the sentinel lymph node biopsy treatment arm, respectively (P = 0.821). CONCLUSION: In patients with T1-2 breast cancer and one to two macrometastatic sentinel lymph nodes treated with mastectomy, the overall survival and recurrence-free survival rates of patients treated with sentinel lymph node biopsy only were not inferior to those treated with axillary lymph node dissection. To strengthen the conclusion of the trial, the enrolment of patients treated with mastectomy was reopened as a single-arm experimental study. REGISTRATION NUMBER: NCT05160324 (http://www.clinicaltrials.gov).

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

PURPOSE: IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. METHODS: Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100 days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. RESULTS: We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7 months vs. not reached, p = 0.0146) and OS time (32.6 months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). CONCLUSION: MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

Preservation of Axillary Lymph Nodes Compared with Complete Dissection in T1-2 Breast Cancer Patients Presenting One or Two Metastatic Sentinel Lymph Nodes: The SINODAR-ONE Multicenter Randomized Clinical Trial.

BACKGROUND: The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse. METHODS: Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). RESULTS: The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936). CONCLUSIONS: The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.

JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function.

RATIONALE: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive. OBJECTIVE: We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions. METHODS AND RESULTS: Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of ß-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A-C/EBP-α-mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer. CONCLUSIONS: We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction. Graphic Abstract: An graphic abstract is available for this article.

Digital Pathology During the COVID-19 Outbreak in Italy: Survey Study.

BACKGROUND: Transition to digital pathology usually takes months or years to be completed. We were familiarizing ourselves with digital pathology solutions at the time when the COVID-19 outbreak forced us to embark on an abrupt transition to digital pathology. OBJECTIVE: The aim of this study was to quantitatively describe how the abrupt transition to digital pathology might affect the quality of diagnoses, model possible causes by probabilistic modeling, and qualitatively gauge the perception of this abrupt transition. METHODS: A total of 17 pathologists and residents participated in this study; these participants reviewed 25 additional test cases from the archives and completed a final psychologic survey. For each case, participants performed several different diagnostic tasks, and their results were recorded and compared with the original diagnoses performed using the gold standard method (ie, conventional microscopy). We performed Bayesian data analysis with probabilistic modeling. RESULTS: The overall analysis, comprising 1345 different items, resulted in a 9% (117/1345) error rate in using digital slides. The task of differentiating a neoplastic process from a nonneoplastic one accounted for an error rate of 10.7% (42/392), whereas the distinction of a malignant process from a benign one accounted for an error rate of 4.2% (11/258). Apart from residents, senior pathologists generated most discrepancies (7.9%, 13/164). Our model showed that these differences among career levels persisted even after adjusting for other factors. CONCLUSIONS: Our findings are in line with previous findings, emphasizing that the duration of transition (ie, lengthy or abrupt) might not influence the diagnostic performance. Moreover, our findings highlight that senior pathologists may be limited by a digital gap, which may negatively affect their performance with digital pathology. These results can guide the process of digital transition in the field of pathology.

Frameless stereotactic biopsy for precision neurosurgery: diagnostic value, safety, and accuracy.

BACKGROUND: Stereotactic biopsy is consistently employed to characterize cerebral lesions in patients who are not suitable for microsurgical resection. In the past years, technical improvement and neuroimaging advancements contributed to increase the diagnostic yield, the safety, and the application of this procedure. Currently, in addition to histological diagnosis, the molecular analysis is considered essential in the diagnostic process to properly select therapeutic and prognostic algorithms in a personalized approach. The present study reports our experience with frameless stereotactic brain biopsy in this molecular era. METHODS: One hundred forty consecutive patients treated from January 2013 to September 2018 were analyzed. Biopsies were performed using the Brainlab Varioguide® frameless stereotactic system. Patients' clinical and demographic data, the time of occupation of the operating room, the surgical time, the morbidity, and the diagnostic yield in providing a histological and molecular diagnosis were recorded and evaluated. RESULTS: The overall diagnostic yield was 93.6% with nine procedures resulting non-diagnostic. Among 110 patients with glioma, the IDH-1 mutational status was characterized in 108 cases (98.2%), resulting wild-type in all subjects but 3; MGMT methylation was characterized in 96 cases (87.3%), resulting present in 60 patients, and 1p/19q codeletion was founded in 6 of the 20 cases of grade II-III gliomas analyzed. All the specimens were apt for molecular analysis when performed. Bleeding requiring surgical drainage occurred in 2.1% of the cases; 8 (5.7%) asymptomatic hemorrhages requiring no treatment were observed. No biopsy-related mortality was recorded. Median length of hospital stay was 5 days (IQR 4-8) with mean surgical time of 60.77 min (± 23.12) and 137.44 ± 24.1 min of total occupation time of the operative room. CONCLUSIONS: Stereotactic frameless biopsy is a safe, feasible, and fast procedure to obtain a histological and molecular diagnosis.

Prediction of Isocitrate Dehydrogenase Genotype in Brain Gliomas with MRI: Single-Shell versus Multishell Diffusion Models.

Purpose The primary aim of this prospective observational study was to assess whether diffusion MRI metrics correlate with isocitrate dehydrogenase (IDH) status in grade II and III gliomas. A secondary aim was to investigate whether multishell acquisitions with advanced models such as neurite orientation dispersion and density imaging (NODDI) and diffusion kurtosis imaging offer greater diagnostic accuracy than diffusion-tensor imaging (DTI). Materials and Methods Diffusion MRI (b = 700 and 2000 sec/mm2) was performed preoperatively in 192 consecutive participants (113 male and 79 female participants; mean age, 46.18 years; age range, 14-77 years) with grade II (n = 62), grade III (n = 58), or grade IV (n = 72) gliomas. DTI, diffusion kurtosis imaging, and NODDI metrics were measured in regions with or without hyperintensity on diffusion MR images and compared among groups defined according to IDH genotype, 1p/19q codeletion status, and tumor grade by using Mann-Whitney tests. Results In grade II and III IDH wild-type gliomas, the maximum fractional anisotropy, kurtosis anisotropy, and restriction fraction were significantly higher and the minimum mean diffusivity was significantly lower than in IDH-mutant gliomas (P = .011, P = .002, P = .044, and P = .027, respectively); areas under the receiver operating characteristic curve ranged from 0.72 to 0.76. In IDH wild-type gliomas, no difference among grades II, III, and IV was found. In IDH-mutant gliomas, no difference between those with and those without 1p/19q loss was found. Conclusion Diffusion MRI metrics showed correlation with isocitrate dehydrogenase status in grade II and III gliomas. Advanced diffusion MRI models did not add diagnostic accuracy, supporting the inclusion of a single-shell diffusion-tensor imaging acquisition in brain tumor imaging protocols. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Prognostic value of molecular and imaging biomarkers in patients with supratentorial glioma.

PURPOSE: We evaluated the relationship between 11C-methionine PET (11C-METH PET) findings and molecular biomarkers in patients with supratentorial glioma who underwent surgery. METHODS: A consecutive series of 109 patients with pathologically proven glioma (64 men, 45 women; median age 43 years) referred to our Institution from March 2012 to January 2015 for tumour resection and who underwent preoperative 11C-METH PET were analysed. Semiquantitative evaluation of the 11C-METH PET images included SUVmax, region of interest-to-normal brain SUV ratio (SUVratio) and metabolic tumour volume (MTV). Imaging findings were correlated with disease outcome in terms of progression-free survival (PFS), and compared with other clinical biological data, including IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation. The patients were monitored for a mean period of 16.7 months (median 13 months). RESULTS: In all patients, the tumour was identified on 11C-METH PET. Significant differences in SUVmax, SUVratio and MTV were observed in relation to tumour grade (p < 0.001). IDH1 mutation was found in 49 patients, 1p/19q codeletion in 58 patients and MGMT promoter methylation in 74 patients. SUVmax and SUVratio were significantly inversely correlated with the presence of IDH1 mutation (p < 0.001). Using the 2016 WHO classification, SUVmax and SUVratio were significantly higher in patients with primary glioblastoma (IDH1-negative) than in those with other diffuse gliomas (p < 0.001). Relapse or progression was documented in 48 patients (median PFS 8.7 months). Cox regression analysis showed that SUVmax and SUVratio, tumour grade, tumour type on 2016 WHO classification, IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation were significantly associated with PFS. None of these factors was found to be an independent prognostic factor in multivariate analysis. CONCLUSION: 11C-METH PET parameters are significantly correlated with histological grade and IDH1 mutation status in patients with glioma. Grade, pathological classification, molecular biomarkers, SUVmax and SUVratio were prognostic factors for PFS in this cohort of patients. The trial was registered with ClinicalTrials.gov (registration: NCT02518061).

The diffusion-weighted imaging and 11-C-methionine positron emission tomography depiction of an endodermal cyst at the cervico-medullary junction.

A case of a 52-year-old male with left-sided neck pain, vertigo and gait instability is reported. A MRI scan revealed an intra-dural mass at the cervico-medullary junction, further characterised by diffusion-weighted imaging and 11-C-methionine positron emission tomography. Pathological diagnosis was endodermal cyst. The clinico-surgical relevance of the imaging findings is discussed.

18 F-FET PET/CT in Calcifying Pseudoneoplasm of the Neuraxis : First Case.

ABSTRACT: A 66-year-old man has been treated in a psychiatric department for 4-5 years for a depressive syndrome, which is associated with poor motor initiative, confusional state, and dysosmia. Dynamic 18 F-FET PET/CT showed only faint uptake of radiotracer just above the background on the left frontal calcific lesion. The time-activity curve of the neoplasms showed a descending pattern. After a left fronto-orbitary minicraniotomy surgery, histology examination concluded for a rare calcifying pseudoneoplasm of the neuraxis (CAPNON). To our knowledge, no data are available on the metabolic behavior of CAPNON in 18 F-FET PET/CT. This case highlighted that a faint uptake and descending pattern on dynamic 18 F-FET PET/CT may be helpful in suspected CAPNON before surgery.

The Impact of Different Patterns of Residual Disease on Long-Term Oncological Outcomes in Breast Cancer Patients Treated with Neo-Adjuvant Chemotherapy.

BACKGROUNDS: The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation between these patterns and oncological results was described. Our aims were to define the predictive factors for different patterns of residual disease and compare the outcomes between the scattered versus the circumscribed pattern. METHODS: We reviewed 219 postoperative surgical specimens. Patients were divided into two groups: scattered versus circumscribed. Disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were analyzed. RESULTS: The scattered and circumscribed patterns were assessed in 111 (50.7%) and 108 (49.3%) patients. Two independent predictive factors for the circumscribed pattern were identified: discontinuation of NAC cycles (p = 0.011), and tumor size post-NAC >18 mm (p = 0.022). No difference was observed in terms of DFS and DDFS. Patients with the scattered pattern exhibited a statistically significant better OS. Discontinuation of NAC cycles, tumor size >18 mm, triple-negative BC, and ypN+ were associated with increased recurrence and poorer survival. CONCLUSIONS: Discontinuation of NAC cycles and tumor size are independent factors associated with patterns of residual disease. The scattered pattern presents better survival. Understanding the relationship between NAC, the residual pattern, and differences in survival outcomes offers the potential to optimize the therapeutic approaches.

Growth and rupture of an intracranial aneurysm: the role of wall aneurysmal enhancement and CD68.

Introduction: Intracranial aneurysms occur in 3%-5% of the general population. While the precise biological mechanisms underlying the formation, growth, and sudden rupture of intracranial aneurysms remain partially unknown, recent research has shed light on the potential role of inflammation in aneurysm development and rupture. In addition, there are ongoing investigations exploring the feasibility of employing new drug therapies for controlling the risk factors associated with aneurysms. CD68, a glycosylated glycoprotein and the human homolog of macrosialin, is prominently expressed in monocyte/macrophages within inflamed tissues and has shown potential application in oncology. An observational study was conducted with the aim of comparing the histological characteristics of aneurysm walls with preoperative MRI scans, specifically focusing on CD68 activity. Method: An observational pilot study was conducted to investigate the histological characteristics of the aneurysm wall that could be potentially associated with aneurysm growth and rupture. A total of 22 patients diagnosed with ruptured and unruptured intracranial aneurysms who had undergone conventional clipping between January 2017 and December 2022 were included in the study. Results: A histopathological analysis of the aneurysm wall was performed in all patients, particularly focusing on the presence of CD68. A preoperative MRI with gadolinium was conducted in 10 patients with unruptured aneurysms and six patients with ruptured aneurysms. An emergency clipping was performed in the remaining six patients. The results showed that CD68 positivity and wall enhancement were significantly associated with intracranial aneurysm wall degeneration, growth, and rupture. Conclusion: The histological and radiological inflammatory findings observed in the wall of cerebral aneurysms, as well as the CD68 positivity, are significantly associated with the risk of intracranial aneurysm growth and rupture. This study highlights the crucial importance of considering clinical and medical data when making treatment decisions for intracranial aneurysms. Furthermore, it emphasizes the relevance of evaluating wall enhancement in MRI scans as part of the diagnostic and prognostic process.

Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients.

INTRODUCTION: Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns. MATERIALS AND METHODS: Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method. RESULTS: Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC <40%; no difference was observed in terms of OS between RTC <40% and RTC ≥40% groups. CONCLUSIONS: Tumor stage before NAC, BC sub-type, and vascular invasion are significant and independent factors associated with pCR. Patients with pCR and with RTC <40% have longer DFS, DDFS, and OS compared with patients with pPR.

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

PURPOSE: We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL). EXPERIMENTAL DESIGN: HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure. RESULTS: A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs. CONCLUSIONS: We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.

Advancing the PD-L1 CPS test in metastatic TNBC: Insights from pathologists and findings from a nationwide survey.

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC.

Breast conserving surgery versus salvage mastectomy for ipsilateral breast cancer recurrence: a propensity score matching analysis.

Salvage mastectomy is regarded as the treatment of first choice for ipsilateral breast cancer recurrence (IBCR), even if a second breast conserving surgery (BCS) is feasible. The purpose of this study was to compare the long-term oncological outcomes of IBCR patients who had undergone either mastectomy or second BCS, performing a propensity score matching (PSM) analysis to reduce the selection bias. All the consecutive patients with IBCR were retrospectively reviewed and divided into two different groups of treatment: repeat BCS versus salvage mastectomy. The propensity score predicting the probability of surgical treatment was determined for each patient and a 1:1 matching was performed. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. A total of 309 patients underwent surgical treatment for IBCR. After PSM, 108 patients treated with repeat BCS and 108 patients treated with salvage mastectomy were included in the analysis. There was no significant difference in terms of DFS between patients with IBCR receiving repeat BCS or salvage mastectomy (p = 0.167). However, patients with IBCR undergoing second BCS had significantly better DDFS, OS, and BCSS compared to salvage mastectomy (p < 0.001). Salvage mastectomy should not be considered the optimal treatment for IBCR and it does not seem to improve prognosis compared to repeat conserving surgery. Second BCS for IBCR is a safe option with encouraging long-term oncological outcomes and should be proposed to all patients, when technically feasible.

Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer.

We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.

Re-irradiation for recurrent high grade glioma (HGG) patients: Results of a single arm prospective phase 2 study.

BACKGROUND AND PURPOSE: Standard of care for recurrent high grade glioma (HGG) is missing. Several treatment options have been investigated including re-irradiation (re-RT). Results are promising but provided by retrospective studies. We designed a single arm prospective phase II study aiming to evaluate efficacy, and toxicity of re-irradiation. MATERIALS AND METHODS: Adults patients with good performance status, HGG diagnosis reclassified according to the new 2021 fifth edition WHO CNS classification, an interval time (IT) from previous RT ≥ 6 months were included. Outcome was evaluated by MRI imaging at 1 month, and every 3 months thereafter. Toxicities were evaluated in terms of radionecrosis occurrence, and neurocognitive status. RESULTS: Ninety recurrent HGG patients were treated, 11 oligodendroglioma grade 3, 18 astrocytoma grade 3 and 4, and 61 glioblastoma grade 4. The median age was 54 years, and majority had KPS 90-100. The median IT between first-RT and re-RT was 24 months. Re-surgery has been performed in 56.6%, and chemotherapy in 53.3%. The median follow up time was 64 months; median overall survival (OS) time,1,2,3-year OS rates were 17 months (95%CI 14-19), 66.7%±4.9, 32.6%±5.0, and 22.2 ± 4.7. Prognostic factors impacting on survival were age (p = 0.0154), IT between first RT and re-RT (p = 0.0051), glioma grade (p = 0.0090), and IDH status (p = 0.0001). Radionecrosis grade 2-3 occurred in 9 (10%) patients; neurocognitive functions remained stable until disease progression. CONCLUSION: Re-RT proved to be a safe and feasible treatment option with low toxicity. Younger patients with grade 3 IDH mutated gliomas, and a longer IT had the better outcome. TRIAL REGISTRATION NUMBER: NCT02567539.