PD-L1 testing in metastatic triple negative breast cancer: Results of an Italian survey.

BACKGROUND: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers. Atezolizumab was approved for patients with metastatic triple-negative breast cancers whose tumors express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 pathology departments of the Lazio Region during a six-month period. METHODS: The survey comprised 12 questions regarding the availability of SP142 in the pathology departments, the percentage of positive tests, the difficulties of pathologists in cases close to cut-off value and the tested samples. RESULTS: The SP142 assay was available in only eight centers. In case of positive result, most centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to ⩽ 5%, with values close to the cut-off point (⩾ 1% or < 1%) being the greatest challenge.Most of the centers (6/8, 75%) tested material from both their own and other hospitals. In most centers, the evaluations were performed either on primary tumors or metastasis, in particular lymph nodes (5/8, 62.5%), followed by lung (3/8, 37.5%) and liver (1/8, 12.5%) metastasis. CONCLUSION: Our results raise some important issues concerning the evaluation of PD-L1 in the "real-life" setting, providing strategies for its implementation.

Immune responses and clinical outcomes following the third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in advanced breast cancer patients receiving targeted therapies: a prospective study.

Purpose: Metastatic breast cancer patients are the most prevalent oncology population with advanced disease facing COVID-19 pandemic. Immune responses after mRNA-based vaccination during treatment with CDK4/6 inhibitors or HER2-directed agents remain unclear. We conducted a prospective analysis to elucidate changes in antibody titers and lymphocyte counts following full course of mRNA-BNT162b2 (tozinameran) vaccination in recipients undergoing these targeted therapies. Methods: Patients who had received a booster dosing and had been treated for at least 6 months were eligible. Antibody titers against SARS-CoV-2 spike protein were measured at four subsequent time points. Immunophenotyping of circulating lymphocytes was performed before the third dose of tozinameran and four weeks later to quantify the absolute counts of CD3+CD4+ T-helper cells, CD3+CD8+ T-cytotoxic cells, CD19+ B cells, and CD56+CD16+ NK cells. We also assessed the incidence of breakthrough infections and investigated whether immune changes affect time-to-treatment failure (TTF) after booster vaccination. Results: The current analysis included 69 patients, of whom 38 (55%) and 31 (45%) were being treated with CDK4/6 inhibitors and HER2-targeted therapies, respectively. All participants received a third dose of tozinameran between September 23 and October 7, 2021. Multivariate analysis revealed that CDK4/6 inhibition predicted a significantly impaired humoral response after the booster dose. This detrimental effect was also evident for T-helper cell counts before the third immunization, but it disappeared in the subsequent evaluation. After a median follow-up of 22.3 months, we observed 19 (26%) cases of COVID-19 outbreaks, all experiencing favorable clinical outcomes. Univariate analysis showed a significant association between the onset of SARS-CoV-2 infections and the use of CDK4/6 inhibitors, as well as with an impaired antibody and T-helper cell response. Only the last two covariates remained independent predictors after multivariate testing. Dynamic variations in antibody titers and T-helper cell counts did not affect TTF in multivariate regression analysis. Conclusions: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition.

Neuroglobin: A New Possible Marker of Estrogen-Responsive Breast Cancer.

The expression of the α-subtype of Estrogen Receptor (ERα) characterizes most breast cancers (more than 75%), for which endocrine therapy is the mainstay for their treatment. However, a high percentage of ERα+ breast cancers are de novo or acquired resistance to endocrine therapy, and the definition of new targets for improving therapeutic interventions and the prediction of treatment response is demanding. Our previous data identified the ERα/AKT/neuroglobin (NGB) pathway as a common pro-survival process activated in different ERα breast cancer cell lines. However, no in vivo association between the globin and the malignity of breast cancer has yet been done. Here, we evaluated the levels and localization of NGB in ERα+ breast ductal carcinoma tissue of different grades derived from pre-and post-menopausal patients. The results indicate a strong association between NGB accumulation, ERα, AKT activation, and the G3 grade, while no association with the menopausal state has been evidenced. Analyses of the data set (e.g., GOBO) strengthen the idea that NGB accumulation could be linked to tumor cell aggressiveness (high grade) and resistance to treatment. These data support the view that NGB accumulation, mainly related to ER expression and tumor grade, represents a compensatory process, which allows cancer cells to survive in an unfavorable environment.

Extracellular Neuroglobin as a Stress-Induced Factor Activating Pre-Adaptation Mechanisms against Oxidative Stress and Chemotherapy-Induced Cell Death in Breast Cancer.

Components of tumor microenvironment, including tumor and/or stromal cells-derived factors, exert a critical role in breast cancer (BC) progression. Here we evaluated the possible role of neuroglobin (NGB), a monomeric globin that acts as a compensatory protein against oxidative and apoptotic processes, as part of BC microenvironment. The extracellular NGB levels were evaluated by immunofluorescence of BC tissue sections and by Western blot of the culture media of BC cell lines. Moreover, reactive oxygen species (ROS) generation, cell apoptosis, and cell migration were evaluated in different BC cells and non-tumorigenic epithelial mammary cells treated with BC cells (i.e., Michigan Cancer Foundation-7, MCF-7) conditioned culture media and extracellular NGB. Results demonstrate that NGB is a component of BC microenvironment. NGB is released in tumor microenvironment by BC cells only under oxidative stress conditions where it can act as autocrine/paracrine factor able to communicate cell resilience against oxidative stress and chemotherapeutic treatment.

Adjuvant aromatase inhibitor therapy in early breast cancer: what factors lead patients to discontinue treatment?

BACKGROUND: Aromatase inhibitors (AIs) are standard hormone therapy (HT) for the adjuvant treatment of postmenopausal endocrine-sensitive early breast cancer. Treatment discontinuation due to toxicity is an important issue that may help clinicians identify effective clinical interventions to allow adequate treatment duration. We reviewed the main reasons for interruption of AIs at our institution from 2006 to 2009. METHODS: 236 patients treated with adjuvant AIs were eligible for analysis. Median age was 64 years (35-89), median follow-up 53 months (6-60). Prior adjuvant chemotherapy was taxane based in 47 patients and anthracycline based in 43 patients. 118 patients had received letrozole, 101 anastrozole, and 17 exemestane. RESULTS: Twenty-four patients (10%) needed discontinuation of the first AI assigned as a result of toxicity. Grade 2/3 arthralgia was the main reason for discontinuation in 13/24 patients. No differences in the incidence of arthralgia were noted in patients who had received taxanes or anthracyclines. Headache, alopecia, itching, diffuse skin reaction, allergic reaction with hypertensive crisis, xerostomia and xerophthalmia, insomnia and somnolence were the other reasons for discontinuation. In multivariate logistic regression analysis, age (65 years) and HT were independent factors associated with the onset of arthralgia (p = 0.006 and p = 0.008, respectively; OR 2.65, 95% CI 1.32-5.31). Alternative HT (AI or tamoxifen) was offered to patients who wanted or needed to permanently interrupt the ongoing drug. CONCLUSIONS: In our analysis, 10% of patients discontinued the first AI assigned because of toxicity. Median time course of all adverse events leading to HT discontinuation was 155 days and 135 days for arthralgia. A switch to alternative HT with toxicity monitoring is a recommended option for avoiding premature and permanent interruption of an effective treatment.

Epirubicin and docetaxel as first-line treatment for hormonal receptor positive metastatic breast cancer: the predictive value of luminal subtype: a retrospective cohort analysis.

BACKGROUND: We retrospectively evaluated the efficacy of first-line epirubicin and docetaxel in patients with metastatic, hormonal receptor (HR)-positive, and human epidermal growth factor receptor-2-negative breast cancer. A subgroup analysis evaluated the predictive value of immunohistochemistry-defined luminal subtype. METHODS: We included patients with at least one visceral and measurable site of metastatic disease. Patients were grouped as luminal A (HR(+) and Ki67<13%) or luminal B (HR(+) and Ki67>13%). RESULTS: Forty-four patients were entered and prognostic variables were similar between the subgroups. Luminal B patients achieved higher objective response rate than luminal A (69% versus 19%; P = 0.001), longer time to progression (12.2 months versus 8.6 months; P = 0.039), and longer overall survival (24.6 months versus 19.5 months; P = 0.041). The multivariate analysis confirmed the predictive value of luminal B subtype for longer time to progression. CONCLUSIONS: Identification by Ki67 labelling index of human epidermal growth factor receptor-2-negative luminal A could predict a substantial benefit from systemic chemotherapy. Endocrine therapy would be the most appropriate therapy for luminal A tumours.

Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of immunohistochemically defined subtypes.

BACKGROUND: We evaluated the efficacy of gemcitabine and carboplatin for patients affected by pretreated metastatic breast cancer. A subgroup analysis was performed to evaluate the predictive value of immunohistochemically defined breast cancer subtypes. METHODS: We included human epidermal growth factor 2 (HER-2) negative metastatic breast cancer resistant to previous anthracycline-based and taxane-based chemotherapy, and HER-2 positive metastatic breast cancer with at least two progressions of disease during protracted trastuzumab-based therapy. Treatment consisted of gemcitabine (1000 mg/m(2) intravenous (iv) on days 1 and 8) and carboplatin (area under the curve 5 iv on day 1) applied every 3 weeks. RESULTS: Forty-two patients were registered. Disease control was 58%, with a median time-to-progression (TTP) of 7 months (range 1-12) and a median overall survival of 10.5 months (range 1-34). Patients were grouped as triple negative (ER and PR negative, HER-2 negative), HER-2 (HER-2 positive, ER and PR negative), luminal B (ER and/or PR positive and either HER-2 positive and/or high Ki67), and luminal A (ER and/or PR positive and HER-2 negative and low Ki67). For luminal A patients, disease control was lower (luminal A 34 vs. others 67%; P = 0.02), TTP was shorter (luminal A 2.4 months vs. others 6.3 months, P = 0.015), and overall survival was shorter (luminal A 7.5 months vs. others 11.7 months, P = 0.034) than for other subtypes. CONCLUSIONS: Gemcitabine and carboplatin are effective for pretreated patients with metastatic breast cancer. Luminal A subtype seems to fare poorly compared with other subtypes. Specific difference in gene expression might account for the different outcome.