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About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of >10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p  = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

Approximately a half of breast tumors classified as HER2-negative exhibit HER2-low-positive expression. We recently described a high instability of HER2-low-positive expression from primary breast cancer (BC) to relapse. Previous studies reporting discordance in HER2 status between baseline biopsy and residual disease (RD) in patients undergoing neoadjuvant treatment did not include the HER2-low-positive category. The aim of this study is to track the evolution of HER2-low-positive expression from primary BC to RD after neoadjuvant treatment. Patients undergoing neoadjuvant treatment with available baseline tumor tissue and matched samples of RD (in case of no pCR) were included. HER2-negative cases were sub-classified as HER2-0 or HER2-low-positive (IHC 1+ or 2+ and ISH negative). Four-hundred forty-six patients were included. Primary BC phenotype was: HR-positive/HER2-negative 23.5%, triple-negative (TN) 35%, HER2-positive 41.5%. HER2-low-positive cases were 55.6% of the HER2-negative cohort and were significantly enriched in the HR-positive/HER2-negative vs. TN subgroup (68.6% vs. 46.8%, p = 0.001 χ2 test). In all, 35.3% of non-pCR patients (n = 291) had a HER2-low-positive expression on RD. The overall rate of HER2 expression discordance was 26.4%, mostly driven by HER2-negative cases converting either from (14.8%) or to (8.9%) HER2-low-positive phenotype. Among HR-positive/HER2-negative patients with HER2-low-positive expression on RD, 32.0% and 57.1% had an estimated high risk of relapse according to the residual proliferative cancer burden and CPS-EG score, respectively. In conclusion, HER2-low-positive expression showed high instability from primary BC to RD after neoadjuvant treatment. HER2-low-positive expression on RD may guide personalized adjuvant treatment for high-risk patients in the context of clinical trials with novel anti-HER2 antibody-drug conjugates.

Although 1% is the recommended cut-off to define estrogen receptor (ER) positivity, a 10% cut-off is often used in clinical practice for therapeutic purposes. We here evaluate clinical outcomes according to ER levels in a monoinstitutional cohort of non-metastatic triple-negative breast cancer (BC) patients undergoing (neo)adjuvant chemotherapy. Clinicopathological data of 406 patients with ER < 10% HER2-negative BC treated with (neo)adjuvant chemotherapy between 01/2000 and 04/2019 were collected. Patients were categorized in ER-negative (ER < 1%; N  = 364) and ER-low positive (1–9%, N  = 42). At a median follow-up of 54 months, 88 patients had relapsed and 64 died. No significant difference was observed in invasive relapse-free survival (iRFS) and overall survival (OS) according to ER expression levels, both at univariate and multivariate analysis (5-years iRFS 74.0% versus 73.1% for ER-negative and ER-low positive BC, respectively, p  = 0.6; 5-years OS 82.3% versus 76.7% for ER-negative and ER-low positive BC, respectively, p  = 0.8). Among the 165 patients that received neoadjuvant chemotherapy, pathological complete response rate was similar in the two cohorts (38% in ER-negative, 44% in ER-low positive, p  = 0.498). In conclusion, primary BC with ER1–9% shows similar clinical behavior to ER 1% BC. Our results suggest the use of a 10% cut-off, rather than <1%, to define triple-negative BC.

Background Tumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available. Methods Secondary lesions from 94 BC patients, 43 triple-negative (TN) and 51 HER2-positive, were evaluated for TILs and expression of CD8, FOXP3, and PD-L1 by immunohistochemistry. Results TILs levels on metastasis were generally low (median 5%) and did not differ between TN and HER2+ tumors. Younger patients showed significantly lower TILs ( p  = 0.002). In HER2+ patients, TILs were higher in lung metastases as compared to other sites ( p  = 0.038). TILs composition was different across metastatic sites: skin metastases presented higher FOXP3 ( p  = 0.002) and lower CD8/FOXP3 ratio ( p  = 0.032). Patients treated for metastatic BC prior to biopsy had lower CD8 (overall: p  = 0.005, HER2+: p  = 0.011, TN: p  = 0.075). In TN patients, median overall survival (OS) was 11.8 and 62.9 months for patients with low and high TILs, respectively (HR 0.29, 95%CI 0.11–0.76, log-rank p  = 0.008). CD8/FOXP3 ratio was also prognostic in TN patients (median OS 8.0, 13.2, and 54.0 months in 1st, 2nd and 3th tertile, log-rank p  = 0.019). Both TILs and CD8/FOXP3 ratio were independent factors at multivariate analysis. Counterintuitively, in HER2+ BC, low TILs tumors showed better prognosis (median OS 53.7 vs 39.9 months in TILs low and TILs high, not statistically significant). Conclusions Our findings indicate the relevance of TILs as prognostic biomarker for TNBC even in the advanced setting and provide novel hypothesis-generating data on potential sources of immune heterogeneity of metastatic BC.

Weekly paclitaxel and trastuzumab (APT regimen) represents the standard treatment for most stage I HER2+ breast cancer (BC) patients based on results of the single arm phase II APT trial. Confirmation of long-term outcomes in real-world cohorts is of interest. This retrospective study included patients with early HER2 + BC (pT ≤ 3 cm; pN0/N1mic) treated with APT regimen. This study included 276 patients; most presented hormone receptor (HR) positive (75%, N  = 207) and grade 3 tumors (65.6%, N  = 181). The majority had pT ≤ 2 cm (92.4%, N  = 255), no nodal involvement (93.1%, N  = 257), with only 19 patients (6.9%) presenting N1mic. Anatomical stage was: IA 86.2% ( N  = 238), IB 6.2% ( N  = 17), and IIA 7.6% ( N  = 21). At a median follow-up of 4.4 years, 3-year recurrence free survival (RFS) was 97.3% (95% CI 95.1–99.5), 3-year distant relapse free survival (DRFS) was 98.2% (95% CI 96.4–100), and 3-year invasive breast cancer free survival (IBCFS) rate was 97.1% (95% CI 94.7–99.5). A statistically significant difference in RFS was observed according to anatomical stage (  p  < 0.001). This real-world study confirms that APT regimen is associated with excellent outcomes in stage IA HER2 + BC patients, while caution is warranted for patients with stage IB or IIA disease.

Hormone receptor-positive (HR + )/HER2-negative (HER2 − ) early breast cancers (BCs) are typically considered immunologically cold. However, combining immune checkpoint inhibitors (ICIs) with chemotherapy has shown to improve pathological complete response (pCR) in high-risk patients. Understanding the relationship between immune activation and tumor biology may help identify HR + /HER2 − BC patients most likely to benefit from such combinations. Baseline gene expression data from two neoadjuvant trials (GIADA and LETLOB) including HR + /HER2 − BC patients were analyzed. PAM50 intrinsic subtyping and relevant immune-related gene signatures were calculated. Tumor-infiltrating lymphocytes (TILs) were assessed on baseline samples. Among 109 tumors, PAM50 classified 44% as Luminal-B (LumB), 33% Luminal-A (LumA), 18% Basal-like, and 5% HER2-enriched. TIL levels (available for N  = 101) were generally low (median 2; range 0–100), with higher levels in Basal-like BCs ( p  = 0.008). Basal-like BCs exhibited significantly higher levels of immune-related signatures (CD8 T-cells, Cytotoxic cells, IFN-γ, response to ICI + CT in GeparNuevo) and of PD-1, PD-L1, and PD-L2 genes. No differences were found between LumA and LumB subtypes. TILs and immune signatures showed a significant weak-to-moderate positive correlation with the basal-like signature. HR + /HER2- BCs that display both features of biological aggressiveness and enhanced immunogenicity may represent ideal candidates for the combination of ICI and chemotherapy.

Brain metastases (BMs) are a common complication of advanced breast cancer (BC), and their management has significantly evolved. We evaluated the clinical impact of these changes dividing patients diagnosed with BCBMs at three Institutions according to year of BMs diagnosis: 2000-2007 (group A), 2008-2014 (group B) and 2015-2022 (group C). Stereotactic radiotherapy increased ( p  < 0.001), and WBRT decreased ( p  = 0.010) over time. Among HER2+ BC patients, more received anti-HER2 therapy after BM diagnosis in recent years ( p  < 0.011). Overall survival (OS) did not improve in the entire cohort ( p  = 0.260); however, OS improved in patients with HR-/HER2+ BC (median OS 8.7, 10.1, 23.7 months in group A, B, C, respectively; p  = 0.002). HER2-positivity, not prognostic in group A, became prognostic in group C ( p  < 0.001). While therapy for patients with BCBMs significantly changed over two decades, an OS improvement was observed only in HR-/HER2+ patients, potentially due to increased availability of anti-HER2 therapies with intracranial activity.

Pyoderma gangrenosum is a rare skin necrotizing disease that can arise on a site of surgical trauma. Its pathogenesis has recently been related to dysregulation of the immune system, with inflammatory bowel disease representing the most commonly underlying systemic conditions. Several authors have also reported an association with solid malignancies (especially gastrointestinal and breast cancer). We describe the case of a 39-year-old patient diagnosed with a locally advanced, triple-negative breast cancer who developed a pyoderma gangrenosum on the surgical wound after a CVC implant with systemic complications. As the diagnosis and management of postsurgical pyoderma gangrenosum can be challenging for clinicians, underlying conditions as autoimmune disease and solid tumors have to be considered in order to guide treatment.

BackgroundBrain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM.MethodsPatients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated.ResultsIn the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p < 0.001) and multivariate analysis adjusting for BC-GPA (HR 0.41, 95% CI 0.27–0.61), modified-GPA (HR 0.44, 95% CI 0.29–0.67) and updated-GPA (HR 0.42, 95% CI 0.28–0.63).ConclusionsExtracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.