Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.

Induction chemotherapy with carboplatin and paclitaxel for thymoma in acute respiratory distress due to myasthenia gravis: a case report.

BACKGROUND: Myasthenia gravis (MG) is presented in 30-50% of thymoma cases, particularly in AB, B1 and B2 thymomas, and often associated with antibodies against acetylcholine receptor (AChR). Symptoms include muscle weakness and fatigue, and the severity depends on the muscles involved. Surgery is recommended in resectable thymomas, and after induction chemotherapy in locally advanced cases. The occurrence of acute respiratory insufficiency is a rare but potentially life-threatening event and may preclude the possibility to perform an adequate induction systemic treatment in resectable patients. CASE PRESENTATION: We herein describe a case of a patient who underwent induction chemotherapy with carboplatin and paclitaxel for stage IVa thymoma while on ventilator support for respiratory insufficiency due to MG; the remarkable radiological response and the marked improvement in neurological symptoms made it possible to discontinue ventilatory support and carry out surgery with subsequent complete tumor resection. Unfortunately, due to an infection of the surgical wound, it was not possible to complete the therapeutic process with adjuvant radiotherapy. CONCLUSIONS: Initiation of chemotherapy induction treatment in a patient on mechanical ventilation because of acute MG is a challenge, but this should not hold back from starting a treatment, if it is considered potentially curative. The recommended induction chemotherapy regimen is the combination of doxorubicin, cisplatin, and cyclophosphamide, but in selected cases non-anthracyline regimens may be chosen. Whenever feasible, a multimodal approach including chemotherapy surgery and radiotherapy should be preferred.

ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis.

Endocrine therapy represents the cornerstone of treatment in hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). The natural course of this disease is marked by endocrine resistance, mainly due to Estrogen Receptor 1 (ESR1) acquired mutations. The aim of this study is to evaluate the concordance between ESR1 status in metastatic tumor specimens and matched circulating tumor DNA (ctDNA). Forty-three patients with HR+, HER2-negative mBC underwent both a metastatic tumor biopsy and a liquid biopsy at the time of disease progression. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor specimens and ctDNA from matched plasma were analyzed by droplet digital (dd)PCR for the main ESR1 mutations (Y537S, Y537C, Y537N, D538G, E380Q). We observed a total mutation rate of 21%. We found six mutations on tissue biopsy: Y537S (1), D538G (2), Y537N (1), E380Q (2). Three patients with no mutations in tumor tissue had mutations detected in ctDNA. The total concordance rate between ESR1 status on tumor tissue and plasma was 91%. Our results confirm the potential role of liquid biopsy as a non-invasive alternative to tissue biopsy for ESR1 mutation assessment in mBC patients.

Validation of Residual Proliferative Cancer Burden as a Predictor of Long-Term Outcome Following Neoadjuvant Chemotherapy in Patients with Hormone Receptor-Positive/Human Epidermal Growth Receptor 2-Negative Breast Cancer.

BACKGROUND: The integration of residual cancer burden (RCB) and post-treatment Ki67 as residual proliferative cancer burden (RPCB) has been proposed as a stronger predictor of long-term outcome in unselected patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT), as compared with RCB. However, no specific analysis in hormone-receptor-positive (HR+) human epidermal growth receptor 2-negative (HER2-) BC is available so far. MATERIALS AND METHODS: A cohort of 130 patients with HR+/HER2- BC who underwent NACT between 2000 and 2014 was included. Archival surgical specimens were evaluated for RCB. RPCB was calculated by combining RCB and Ki67 as previously described. Patients were categorized in four RCB and RPCB categories (pathological complete response and tertiles). Disease-free survival (DFS) and overall survival (OS) estimates were determined by Kaplan-Meier analysis and compared using the log-rank test. Overall change of χ2 and c-indexes were used to compare the performance of the prognostic models. RESULTS: RPCB was calculated for 85 patients. After a median follow up of 8.5 years, RCB was associated with OS (p = .048) but not with DFS (p = .152); RPCB was instead significantly associated with both DFS and OS (p = .034 and p < .001, respectively). In terms of OS, RPCB provided a significant amount of prognostic information beyond RCB (∆χ2 5.73, p < .001). In addition, c-index for OS prediction was significantly higher for RPCB as compared with RCB (0.79 vs. 0.61, p = .03). CONCLUSION: This is the first study evaluating RPCB in patients with HR+/HER2- BC treated with NACT. In this independent cohort, RPCB was a strong predictor of DFS and OS. The better performance of RPCB versus RCB was in part due to the ability of RPCB to discriminate a subgroup of patients with a particularly worse prognosis after NACT, who may be candidates for clinical trials evaluating novel adjuvant strategies. IMPLICATIONS FOR PRACTICE: The present work validated residual proliferative cancer burden (RPCB) as a strong predictor of long-term outcome in patients with hormone receptor-positive human epidermal growth receptor 2-negative (HR+/HER2-) breast cancer (BC) treated with neoadjuvant chemotherapy. In addition, results from the present study suggest RPCB as a promising tool to identify patients with HR+/HER2- BC who might potentially benefit from the inclusion in clinical trials evaluating novel or escalated postneoadjuvant treatment strategies because it allowed to discriminate a subgroup of patients with particularly poor prognosis despite having received subsequent endocrine therapy in the adjuvant setting.

Use of scalp cooling device to prevent alopecia for early breast cancer patients receiving chemotherapy: A prospective study.

Chemotherapy-induced alopecia (CIA) affects the majority of patients receiving chemotherapy (CT) for early breast cancer. It is a highly distressing side effect of CT, with psychological and social impact. Primary aim of the present analysis was to assess the efficacy of scalp cooling with DigniCap® in preventing CIA. Success rate was defined as patients' self-reported hair loss <50% according to Dean scale. In this analysis, we reported success rate at 3 weeks after the first CT course and at 3 weeks after the last CT course. Secondary endpoints included self-reported tolerability and patients' judgment on scalp cooling performance. Consecutive early breast cancer patients admitted to Istituto Oncologico Veneto who were recommended to receive neoadjuvant or adjuvant CT, were eligible to undergo scalp cooling during the CT administration within this study. 135 patients were included: 74% received adjuvant CT and 26% neoadjuvant CT (P < .001). The type of CT was: docetaxel-cyclophosphamide (26%), paclitaxel (23%), epirubicin-cyclophosphamide followed by paclitaxel (32%), and paclitaxel followed by epirubicincyclophosphamide (19%). The rate of success in preventing alopecia was 77% (104/135) at 3 weeks from the start of CT and 60% (81/135) at 3 weeks from the end of treatment. Higher success rates were reported in non-anthracycline (71%) compared to anthracycline-containing CT regimens (54%; P < 0.001). Premature discontinuation of scalp cooling was reported in 29/135 patients (21.5%), including withdrawal for alopecia (16/29), for low scalp cooling tolerability (8/29) or both (5/29). Scalp cooling was generally well tolerated. These results overall suggest that the use of scalp cooling is effective in preventing alopecia in the majority of early breast cancer patients receiving neoadjuvant or adjuvant CT, especially for patients undergoing a taxane-based non-anthracycline regimen.

Androgen Receptor Expression and Association With Distant Disease-Free Survival in Triple Negative Breast Cancer: Analysis of 263 Patients Treated With Standard Therapy for Stage I-III Disease.

Background: We evaluated immunohistochemical AR expression and correlation with prognosis in a large series of homogeneously treated patients with primary TNBC. Material and Methods: Patients diagnosed with stage I-III TNBC between 2000 and 2015 at Istituto Oncologico Veneto who received treatment with surgery and neoadjuvant and/or adjuvant chemotherapy were included. Whole tissue slides were stained for AR. AR-positive expression was defined as >1% of positively stained tumor cells. Distant-disease-free survival (DDFS) was calculated from diagnosis to distant relapse or death. Late-DDFS was calculated from the landmark of 3 years after diagnosis until distant relapse or death. Results: We included 263 primary TNBC patients. Mean AR expression was 14% (range 0-100%), and 29.7% (n = 78) of patients were AR+. AR+ vs. AR- cases presented more frequently older age (p < 0.001), non-ductal histology (p < 0.001), G1-G2 (p = 0.003), lower Ki67 (p < 0.001) and lower TILs (p = 0.008). At a median follow up of 81 months, 23.6% of patients experienced a DDFS event: 33.3% of AR+ and 19.5% of AR- patients (p = 0.015). 5 years DDFS rates were 67.2% and 80.6% for AR+ and AR- patients (HR = 1.82 95%CI 1.10-3.02, p = 0.020). AR maintained an independent prognostic role beyond stage, but when TILs were added to the model only stage and TILs were independent prognostic factors. AR was the only factor significantly associated with late-DDFS: 16.4% of AR+ and 3.4% of AR- patients experienced a DDFS after the landmark of 3 years after diagnosis (p = 0.001). Late-DDFS rates at 5 years from the 3-year landmark were 75.8% for AR+ and 95.2% for AR- patients (log-rank p < 0.001; HR = 5.67, 95%CI 1.90-16.94, p = 0.002). Conclusions: AR expression is associated with worse outcome for patients with TNBC. In particular, AR+ TNBC patients are at increased risk of late DDFS events. These results reinforce the rationale of AR targeting in AR+ TNBC.

Neoplastic Pericardial Effusion: A Monocentric Retrospective Study.

Background: Neoplastic pericardial effusion (NPE) is a life-threatening condition that can worsen clinical outcome in cancer patients. The optimal management of NPE has yet to be defined because randomized studies are lacking. Objective: We report a retrospective monoinstitutional experience describing characteristics, management and prognostic factors in NPE patients. Design: We reviewed clinical, pathological, and echocardiographic features, therapeutic strategies, and outcome in NPE patients referred to our institute from August 2011 to December 2017. Measurements: Twenty-nine patients with NPE from solid tumors have been identified: 21 lung, 5 breast, and 3 other cancer patients. Results: Median age was 62 years. Most of the patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (69%) and a symptomatic NPE (69%). In 52% of patients NPE was detected at first diagnosis of metastatic disease, and in 20% of patients pericardium was the only site of metastases. Most of the patients (62%) received systemic therapy, 28% received combined locoregional and systemic therapy, and 10% received locoregional therapy alone. Median overall survival (OS) from NPE diagnosis was 3.9 months. Patients with PS ≥2 had worse OS than patients with better PS <2 (hazard ratio [HR] 3.56, IC 95% 1.19-10.65, p 0.02). Older age, extrapericardial disease, and NPE at progression showed a trend of association with worse OS. Patients treated with locoregional therapy alone showed the shortest median OS (p 0.05). Conclusions: NPE is related to dismal prognosis. Poor PS significantly worsens survival and influences therapeutic approaches. Randomized studies are required to investigate prognostic factors and appropriate clinical management for patients with NPE.

Gastric Linitis Plastica and Peritoneal Carcinomatosis as First Manifestations of Occult Breast Carcinoma: A Case Report and Literature Review.

Gastric linitis plastica is a diffuse involvement of the stomach walls by neoplastic cells. It represents about 3-19% of primitive gastric adenocarcinomas, but it can also be the manifestation of a metastatic disease. Breast cancer is the most frequent malignancy in women, and the metastatic spread to the stomach occurs in less than 10% of the cases. We present an unusual case of gastric linitis plastica and peritoneal carcinomatosis as manifestations of an occult breast cancer in a 53-year-old woman. Imaging and endoscopic evaluation were not able to discriminate a primary from a secondary gastric lesion. The histological evaluation excluded the diagnosis of a primary gastric neoplasia. The IHC profile was consistent with the diagnosis of metastases from the breast cancer. Due to the hormonal receptors' positivity, we started therapy with fulvestrant (500 mg, day 0, 14, and 28 and every 28 days thereafter by intramuscular injection). After 20 months, the same therapy is still ongoing and well tolerated, while the patient is in good condition with improvement of the dysphagia. Almost 2 years after the diagnosis of linitis plastica, the primitive breast lesion is still occult.

Correlation between CA125 levels after sixth cycle of chemotherapy and clinical outcome in advanced ovarian carcinoma.

AIM: To correlate CA125 levels after platinum- and paclitaxel-based chemotherapy with progression-free survival (PFS) and overall survival (OS) in advanced ovarian carcinoma following primary cytoreduction. MATERIALS AND METHODS: The study was conducted on 247 patients. RESULTS: By log-rank test, PFS and OS were related to performance status (PS) (p=0.04 and p=0.00002), residual disease (p=0.00002 and p=0.001), ascites (p=0.00001 and p=0.0003) and post-chemotherapy CA125 using 10.8 U/ml as cut-off (p=0.0001 and p=0.01). PFS was related to post-chemotherapy CA125 assay (cut-off values of 7.1 U/ml (p=0.02), 18.5 U/ml (p<0.000001) and 35.0 U/ml (p=0.0001)). OS was related to FIGO stage (p=0.02). On multivariate analysis, residual disease, ascites and post-chemotherapy CA125 with any selected cut-off were independent prognostic variables for PFS, whereas residual disease, PS and post-chemotherapy CA125 (10.8 U/ml as cut-off) were independent prognostic variables for OS. CONCLUSION: Post-operative CA125 using 10.8 U/ml as cut-off was an independent prognostic variable for both PFS and OS.