Triple-negative breast cancers (TNBCs) are characterized by a poor prognosis and lack of targeted treatments, and thus, new therapeutic strategies are urgently needed. Inhibitors against programmed ...death-1 (PD-1)/PD-1 ligand (PD-L1) have shown significant efficacy in various solid cancers, but their activity against TNBCs remains limited. Here, we report that human TNBCs molecularly stratified for high levels of PD-L1 (PD-L1
) showed significantly enriched expression of immune and cancer stemness pathways compared with those with low PD-L1 expression (PD-L1
). In addition, the PD-L1
cases were significantly associated with a high stemness score (SS
) signature. TNBC cell lines gated for aldehyde dehydrogenase (ALDH) and CD44 stemness markers exhibited increased levels of PD-L1 versus their ALDH-negative and CD44
counterparts, and PD-L1
cells generated significantly more mammospheres than PD-L1
cells. Murine mammary SCA-1-positive tumor cells with PD-L1
expression generated tumors in vivo with higher efficacy than PD-L1
cells. Furthermore, treatment of TNBC cells with selective WNT inhibitors or activators downregulated or upregulated PD-L1 expression, respectively, implying a functional cross-talk between WNT activity and PD-L1 expression. Remarkably, human TNBC samples contained tumor elements co-expressing PD-L1 with ALDH1A1 and/or CD44v6. Additionally, both PD-L1-/SCA1-positive and ALDH1A1-positive tumor elements were found in close contact with CD3-, and PD-1-positive T cells in murine and human tumor samples. Overall, our study suggests that PD-L1-positive tumor elements with a stemness phenotype may participate in the complex dynamics of TNBC-related immune evasion, which might be targeted through WNT signaling inhibition.
Rituximab (Rit) therapy added to involved-field radiation therapy (RT) has been proposed as an effective treatment for stage I-II follicular lymphoma (FL). The results of an observational multicenter ...study on the Rit-RT combination in limited-stage FL are here reported.
Data have been collected from 2 consecutive cohorts of 94 patients with stage I-II FL treated between 1985 and 2011 at 5 Italian institutions. All patients had grade 1-3a FL, a median age of 54 years (range: 25-82). The first 51 patients received RT alone (control group), while the subsequent series of 43 patients received 4 rituximab courses (375 mg/m(2), days 1, 8, 15, 22) before RT (Rit-RT). Molecular disease was evaluated by nested bcl-2/IgH PCR or clonal IgH rearrangement was available in 33 Rit-RT patients.
At a median follow-up of 10.9 years (range: 1.8-22.9), the 10-year progression-free survival (PFS) and overall survival (OS) projections for the whole cohort were 57% and 87.5%, respectively. The 10-year PFS was significantly longer (P<.05) in the Rit-RT group (64.6%) compared to RT alone (50.7%), whereas the 10-year OS projections were not significantly different. On bivariate analysis controlling for stage, there was only a trend toward improved PFS for Rit-RT (HR, 0.55; P=.081). Follicular lymphoma international prognostic index and age were associated with OS but not with PFS on Cox regression analysis. Bone marrow molecular analysis showing PCR positivity at diagnosis was strongly associated with relapse risk upon univariate and multivariate analysis.
This multicenter observational study suggests a potential benefit of adding rituximab to radiation therapy for stage I-II FL. The results of the currently ongoing randomized studies are required to confirm these results. The study underlines the importance of molecular disease monitoring also for patient with limited-stage disease.
This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (
or ...transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m
) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 43.9%; 90% confidence interval (CI:) 30.6-57.9%. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at:
.
Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant ...chemotherapy.
Patients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.
In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.
Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation.
EU Clinical Trial Register, EudraCT number 2012-004956-12.
Background
Since a non-negligible fraction of patients with metastatic melanoma does not experience long-term disease control, even with immunotherapy and targeted therapy, new biomarkers for patient ...stratification and treatment tailoring are needed in this setting.
Objective
We investigated the association of a novel immune-inflammatory blood-based biomarker, the Pan-Immune-Inflammation Value (PIV), with clinical outcomes of patients with metastatic melanoma receiving first-line therapy.
Patients and Methods
We retrospectively included patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and having an available baseline complete blood cell count (CBC). PIV was calculated as: neutrophil count (10
3
/mm
3
) × platelet count (10
3
/mm
3
) × monocyte count (10
3
/mm
3
)/lymphocyte count (10
3
/mm
3
).
Results
A total of 228 patients were included: 119 (52%) had been treated with immunotherapy and 109 (48%) with targeted therapy. PIV was significantly higher in patients with ECOG PS ≥ 1, high disease burden, synchronous metastases, and elevated baseline LDH level. High baseline PIV was independently associated with poor overall survival (adjusted hazard ratio HR: 2.06; 95% confidence interval CI: 1.30–3.29; adjusted
P =
0.002) and progression-free survival (adjusted HR 1.56; 95% CI 1.01–2.41; adjusted
P =
0.044). High PIV was also associated with primary resistance to both immunotherapy (odds ratio OR: 3.98; 95% CI 1.45–12.32;
P =
0.005) and targeted therapy (OR: 8.42; 95% CI 2.50–34.5;
P
< 0.001). PIV showed a promising discrimination ability in terms of AIC and c-index when compared with other CBC-based biomarkers.
Conclusions
PIV may guide the treatment decision process and the development of novel first-line treatment strategies in melanoma, but warrants further study and validation.
CD2+ T lymphocytes obtained from either the donor of bone marrow stromal cells (BMSCs) or a third party were cultured in mixed lymphocyte reactions (MLRs) with either allogeneic dendritic cells (DCs) ...or peripheral blood lymphocytes (PBLs). When autologous or allogeneic BMSCs were added back to T cells stimulated by DCs or PBLs, a significant and dose-dependent reduction of T-cell proliferation, ranging from 60% ± 5% to 98% ± 1%, was evident. Similarly, addition of BMSCs to T cells stimulated by polyclonal activators resulted in a 65% ± 5% (P = .0001) suppression of proliferation. BMSC- induced T-cell suppression was still evident when BMSCs were added in culture as late as 5 days after starting of MLRs. BMSC-inhibited T lymphocytes were not apoptotic and efficiently proliferated on restimulation. BMSCs significantly suppressed both CD4+ and CD8+ T cells (65% ± 5%, P = .0005 and 75% ± 15% P = .0005, respectively). Transwell experiments, in which cell-cell contact between BMSCs and effector cells was prevented, resulted in a significant inhibition of T-lymphocyte proliferation, suggesting that soluble factors were involved in this phenomenon. By using neutralizing monoclonal antibodies, transforming growth factor β1 and hepatocyte growth factor were identified as the mediators of BMSC effects. In conclusion, our data demonstrate that (1) autologous or allogeneic BMSCs strongly suppress T-lymphocyte proliferation, (2) this phenomenon that is triggered by both cellular as well as nonspecific mitogenic stimuli has no immunologic restriction, and (3) T-cell inhibition is not due to induction of apoptosis and is likely due to the production of soluble factors.
The HER2 splice variant characterized by the deletion of exon 16 and denominated as d16HER2, is associated with HER2-positive breast cancer (BC) aggressiveness, stemness, and trastuzumab ...susceptibility and is considered to be a "flag" of HER2 dependence. However, with the exception of quantitative real-time PCR analysis, easily reproducible assays are still lacking to clinically detect and quantify the d16HER2 expression. Further, no data on d16HER2 expression and its potential role are available in HER2-positive gastrointestinal malignancies. Here, we used a novel RNA in situ hybridization technique (BaseScope) to discriminate d16HER2 variant expression from the wild type isoform (WTHER2) and to assess their levels across different HER2-positive histological samples. Our results demonstrate the existence of outliers, with d16HER2 mRNA high scores restricted to HER2-positive gastric cancer (GC) and colorectal cancer (CRC) coupled with increased d16HER2 expression compared with BC. Consistent with previously reported data on BC, experiments performed in HER2-positive GC patient-derived xenografts suggest that increased d16HER2 expression is associated with a clinical benefit/response to single-agent trastuzumab. Therefore, d16HER2 may be considered as a "flag" of HER2 dependence in GC and can be clinically investigated as a marker of trastuzumab susceptibility in several other HER2-driven cancers, including CRC. As a clinical proof-of-concept, we indicate that high d16HER2 mRNA scores are exclusively found in patients with a long-term benefit from trastuzumab exceeding 12 months (clinical "outliers"), and that d16HER2 expression is also increased in circulating tumor-released exosomes obtained from baseline plasma samples of long-term responders.
SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death ...protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.
Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2‐positive ...breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression profiles of transgenic murine BC cell lines expressing the human d16HER2 variant (HER2‐addicted) or human full‐length HER2 (WTHER2; HER2‐nonaddicted) revealed a significant enrichment of glycolysis‐related gene pathways in HER2‐addicted cells. We studied the metabolic content of 22 human HER2‐positive BC by quantitative nuclear magnetic resonance spectroscopy and found that those cases with higher lactate levels were characterized by higher HER2 transcript levels. Moreover, gene expression analyses of HER2‐positive BC samples from a TCGA data set revealed a significant enrichment in glycolysis‐related pathways in high/HER2‐addicted tumors. These data were confirmed by metabolic analyses of human HER2‐positive BC cell lines with high or low HER2 transcript levels, which revealed significantly more active glycolytic metabolism in high HER2 transcript than in low HER2 transcript cells. Overall, our results provide evidence for noninvasive intratumor lactate detection as a potential metabolic biomarker of HER2 addiction and trastuzumab response suggesting the possibility to use in vivo imaging to assess lactate levels and, in turn, select HER2‐positive BC patients who are more likely to benefit from anti‐HER2 treatments.
The purpose of this study was to identify a reliable, noninvasive, and novel biomarker associated with HER2 addiction that reflects the susceptibility to HER2‐specific therapy. Our results provide experimental and relevant support for the preclinical and clinical association between HER2 addiction/trastuzumab susceptibility and intratumor levels of lactate, a key metabolic player in cancer progression that is upregulated early in the development of malignancies. Through molecular and metabolic analyses, we found a statistically significant association among HER2 transcript levels, intratumor lactate levels and response to therapy, thus paving the way for the utilization of Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy as a powerful and independent tool to better tailor anti‐HER2 therapies and improve the outcomes of all patients with HER2‐positive BC.
Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors ...admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P < 0.001). In the multivariable model, hyponatremia was independently associated with poorer OS (HR, 1.66; P < 0.001). According to the multivariable model, a nomogram system was developed and validated in an external set of patients. We weighed over time the influence of hyponatremia on survival of patients with metastatic solid tumors and pointed out the possibility to exploit serum sodium assessment to design integrated prognostic tools. Our study also highlights the need for a deeper characterization of the biological role of extracellular sodium levels in tumor development and progression.
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