Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going

Abstract: Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer (BC) subtype. Gene expression profiling has identified at least six different triple-negative subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic treatment is an effective option of care. The achievement of a pathological complete response represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity. In this review, we provide a brief description of the main predictive biomarkers for tumor response to systemic treatment. Moreover, we review the treatment strategies investigated for TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC patients may be treated on the basis of tumor molecular profile

Impact of anaemia on tumor response to neoadjuvant chemotherapy in breast cancer patients .

BACKGROUND - Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) in patients with breast cancer (BC) predicts long-term outcomes. Anaemia is one of the most common side effects of cytotoxic drugs. Biologically, anaemia induces adaptive responses due to the low intra-tumoral oxygen levels that may be responsible for increase chemotherapy resistance. In literature, data regarding this issue are lacking. AIM - To evaluate the influence of anaemia throughout treatment course on tumour shrinkage induced by NST. METHODS - Patients - 317 patients diagnosed with stage I-III BC treated with NST and with available blood tests were included. Patients and tumor characteristics and treatments information were collected. We focused on Haemoglobin (Hb) level (at baseline, at the end of NST, drop in Hb throughout treatment and duration of anaemia) and its correlation with pCR rate. Anaemia was defined as a drop of Hb under the local limit of normal in women (12 mg/dl). Statistical analysis - Categorical variables were analyzed using chi-square test or Fisher's exact test, continuous variables using t test. Univariate and multivariate analyses were fit to determinate the association between anaemia and pCR rate. A p-value < 0.05 was considered statistically significant; hazard ratio was estimated with 95% of confidence limits. RESULTS- No difference in Hb levels was observed stratifying patients according to nuclear grade, tumor stage, cancer subtypes and chemotherapy regimens. Median baseline Hb was 13.3 g/dl while median Hb level at the end of NST was 10 g/dl. 31 patients had pre-treatment anaemia. 60% of patients developed anaemia during NST period. In the subgroup of anaemic patients, who had a decrease in Hb ≥ 2 g/dl from baseline or anaemia longer than two months, a lower rate of pCR was observed (16% vs 29%, p=0.03 and 16% vs 25%, p=0.01, respectively). Patients with both these characteristics had the lowest rate of pCR (10%, p=0.01). CONCLUSIONS - Anaemia is a negative predictive factor for tumor response in women treated with NST for BC. This evidence suggests that anaemia should be improved in order to improve response to NST

Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death‑1 ligand 1 (PD‑L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD‑L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor‑infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD‑L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD‑L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD‑L1 assessment guidelines to apply in the field of immunotherapy

Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus

Background. Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Patients and Methods. Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. Results. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (, , and ). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. Conclusions. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study

Molecular mechanisms and cellular contribution from lung fibrosis to lung cancer development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung 28 disease (ILD) of unknown etiology, with a median survival of 2-4 years from the time of diagnosis. 29 Although IPF has unknown etiology by definition, there have been identified several risks factors 30 increasing the probability of the onset and progression of the disease in IPF patients such as cigarette 31 smoking and environmental risks factors associated to domestic and occupational exposure. Among 32 them, cigarette smoking together with concomitant emphysema might predispose IPF patients to 33 lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer 34 development. To this purpose, IPF and LC share several cellular and molecular processes driving 35 the progression of both pathologies such as fibroblast transition proliferation and activation, endo- 36 plasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose 37 the IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed 38 as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target 39 molecular pathway. In this review our aim is to describe the updated studies on common cellular 40 and molecular mechanisms between IPF and lung cancer, whose knowledge might help to find 41 novel therapeutic targets for this disease combination

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p &lt; 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p &lt; 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p &lt; 0.0001) or urgent (20.4% vs. 38.5%; p &lt; 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p &lt; 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Safety and efficacy of T-DM1 in HER2 positive metastatic breast cancer patients: a real word experience.

Background: T-DM1 is an antibody–drug conjugate that combines the antitumor effects of trastuzumab with a cytotoxic antimicrotubule agent that is only released in HER-positive tumor cells. It has been approved for the treatment of patients with HER2 positive metastatic breast cancer (MBC) pre-treated with trastuzumab + taxanes or progressing while on adjuvant trastuzumab, after the pivotal phase III trial EMILIA. The aim of this study is to audit the real life experience with T-DM1 at the University Hospital of Modena. Material and methods: All patients treated with T-DM1 in our Institution between May 2014 – February 2016 were retroprospectively collected. All patients registered at the time of analysis were evaluated for safety and efficacy. Treatment toxicities were graded according to CTCAE version 4.0. Efficacy was assessed as per clinical practice. Results: Twenty-two patients have been treated with T-DM1. The median age was 58 years (range 38-77), 50% of them with ECOG 1-2. With regards to tumor characteristics, 72% were hormonal receptor positive BC and 82% of patients had visceral involvement at the beginning of T-DM1. All patients received previous trastuzumab and taxane, 50% received anthracycline-based therapy too. 27% of patients were pre-treated with at least three prior chemotherapy lines for MBC. Pertuzumab was previously administered to one patient, lapatinib to 8 patients. The median number of T-DM1 cycles was 9 (range 1-30), with 50% of patients receiving 5 or more courses. All patients were assessed for efficacy: 36% obtained PR and 18% SD as the best response. The clinical benefit rate (CR+PR+SD>6months) was 45%. The median PFS was 9.0 months (CI 2.8–20.8). Six patients (27%) out of 22 died. Mild grade transaminitis was the most common side effect observed in 50% of patients, followed by fatigue in 41% of patients, thrombocytopenia in 35% and diarrhea in 28%. No grade 3 adverse events were observed, although two hypersensitivity reactions were reported. Conclusions: T-DM1 administered outside the context of a clinical trial is safe, well tolerated, and with reproducible efficacy, consistent with those published in the EMILIA and TH3RESA studies

Oligorecurrent Non-Small-Cell Lung Cancer Treated by Chemo-Radiation Followed by Immunotherapy and Intracranial Radiosurgery: A Case Report and Mini Review of Literature

Locally advanced non-small-cell lung cancer still represents a “grey zone” in terms of the best treatment choice and optimal clinical outcomes. Indeed, most patients may be suitable to receive different treatments with similar outcomes such as chemo-radiotherapy (CHT-RT) followed by immunotherapy (IO) or surgery followed by adjuvant local/systemic therapies. We report a clinical case of a patient submitted to primary thoracic surgery who developed a mediastinal nodal recurrence successfully treated by CHT-RT-IO. Subsequently, a single brain lesion was found to have been successfully treated by single fraction stereotactic ablative radiotherapy. The patient is still on follow-up and she is free from disease having a good quality of life. In this report, we also perform a mini review about the role of CHT-RT followed by IO in treating loco-regional relapse after surgery. The role of SABR after IO is also evaluated, finding that it is safe and well tolerated. More robust and larger clinical data are needed in this particular setting to better define the role of the combination of systemic and local treatments in the management of intrathoracic and intracranial relapse for patients already submitted to CHT-RT followed by immunotherapy