We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast ...cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.
Inclusion criteria were the following: oligometastatic breast cancer with ≤5 metastatic sites, FDG-PET/CT staging, no brain metastases, primary tumor controlled. Radiotherapy could be delivered using stereotactic body radiotherapy (SBRT) technique or fractionated intensity modulated radiotherapy (IMRT). SBRT consisted of 30–45Gy in 3 fractions, while IMRT was delivered to a total dose of 60Gy in 25 fractions. We hypothesized that radical radiation therapy could increase the PFS from 30% (according to the published literature) to 50% at two years.
54 Patients with 92 metastatic lesions were enrolled. Forty-four were treated with SBRT, and 10 with IMRT. Forty-eight (89%) patients received a form of systemic therapy concomitantly to radiation therapy. Sites of metastatic disease were the following: bones 60 lesions, lymph nodes 23 lesions, lung 4 lesions, liver 5 lesions. After a median follow-up of 30months (range, 6–55months), 1- and 2-year PFS was 75% and 53%, respectively. Two-year LC and OS were 97% and 95%, respectively. Radiation therapy was well tolerated, and no Grade ≥3 toxicity was documented. Grade 2 toxicity were pain and fatigue in 2 cases.
Patients with oligometastatic breast cancer treated with radical radiotherapy to all metastatic sites may achieve long-term progression-free survival, without significant treatment-related toxicity. While waiting for data from randomized trials, the use of radical radiation therapy to all metastatic sites in patients with oligometastatic breast cancer should be considered a valuable option, and its recommendation should be individualized.
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, ...since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.
Synopsis
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
CDK6 in complex with cyclin D3 participates in the control of DNA damage response.
CDK6 binds and phosphorylates FOXO3 on serine 325 to control ATR expression.
High CDK6 expression predicts poor survival of EOC patients.
A combination of platinum‐based chemotherapy with pharmacological CDK6 inhibition might be a new therapeutic option for EOC patients.
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In ...oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing
BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the
appearance of polyfunctional CD4
and CD8
T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC
models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4
T cells when patients' lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased
and PD-L1 expression in BC
models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the
vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients.
Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival and motility. The PI3K pathway is considered to ...play an important role in tumorigenesis. Activating mutations of the p110α subunit of PI3K (PIK3CA) have been identified in a broad spectrum of tumors. Analyses of PIK3CA mutations reveals that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we analyze the contribution of the PIK3CA mutations in cancer, and their possible implications for diagnosis and therapy.
The Yin Yang 1 (YY1) transcription factor has a pivotal role in normal biological processes such as development, differentiation, replication and cell proliferation exerting its effects on a huge ...number of genes involved in these processes. Mechanisms of YY1 action are related to its ability to initiate, activate, or repress transcription depending upon the context in which it binds. The role of YY1 played in cancer has been recently explored. This article summarizes the most relevant studies focused on YY1 regulation and dwells on the way how its overexpression may affect the clinical behaviour of several cancer types. Furthermore, the contribution of the up-regulation of YY1 exerted in response to therapeutic-induced apoptosis is discussed.
Stathmin is a p53‐target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG‐EOC) represents the only clear exception to ...this observation. Here, we show that stathmin expression is necessary for the survival of HG‐EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA‐PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA‐PKCS impaired p53MUT–dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA‐PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
In high‐grade epithelial ovarian carcinomas (the most lethal gynecological cancers), p53 gain‐offunction mutation is a driving oncogenic event. Here, Stathmin is shown to control p53 stability by modulating p53mut/DNA‐PK interaction.
To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction).
Patients ...affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old or over and treated with breast conservative surgery for early stage invasive carcinoma.
Seventy-three patients were analyzed. Median follow-up was 40 months. The proposed schedule was well tolerated. No Grade 3 toxicity was documented. Late toxicity was assessable for all the treated patients. Two patients (2.7%) developed Grade 2 pain 6 months after PBI. Four patients (5%) developed asymptomatic fat necrosis. Grade 2 fibrosis was observed in 5 patients (6.7%). No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). No statistical correlation between dosimetric parameters and toxicity was found. Patients who developed Grade 2 radiation fibrosis had not higher radiation volumes to the untreated normal breast than those without fibrosis. Cosmesis was judged good/excellent in the majority of the cases (93%). One patient relapsed locally, and one developed distant metastases, corresponding to a 5-year local control and distant metastases-free survival of 98% and 96.7%, respectively.
35 Gy in 7 daily fractions is an effective and well-tolerated regimen to deliver PBI.
Melanoma is a highly metastatic cancer, and there are no current therapeutic modalities to treat this deadly malignant disease once it has metastasized. Melanoma cancers exhibit B-RAF mutations in up ...to 70% of cases. B-RAF mutations are responsible, in large part, for the constitutive hyperactivation of survival/antiapoptotic pathways such as the MAPK, NF-κB, and PI3K/AKT. These hyperactivated pathways regulate the expression of genes targeting the initiation of the metastatic cascade, namely, the epithelial to mesenchymal transition (EMT). EMT is the result of the expression of mesenchymal gene products such as fibronectin, vimentin, and metalloproteinases and the invasion and inhibition of E-cadherin. The above pathways cross-talk and regulate each other's activities and functions. For instance, the NF-κB pathway directly regulates EMT through the transcription of gene products involved in EMT and indirectly through the transcriptional up-regulation of the metastasis inducer Snail. Snail, in turn, suppresses the expression of the metastasis suppressor gene product Raf kinase inhibitor protein RKIP (inhibits the MAPK and the NF-κB pathways) as well as PTEN (inhibits the PI3K/AKT pathway). The role of B-RAF mutations in melanoma and their direct role in the induction of EMT are not clear. This review discusses the hypothesis that B-RAF mutations are involved in the dysregulation of the NF-κB/Snail/RKIP/PTEN circuit and in both the induction of EMT and metastasis. The therapeutic implications of the dysregulation of the above circuit by B-RAF mutations are such that they offer novel targets for therapeutic interventions in the treatment of EMT and metastasis.
LFB-R603 is a chimeric anti-CD20 mouse/human monoclonal antibody with a human IgG1 constant (Fc) region. In comparison to rituximab, LFB-R603 exhibits a high affinity to the Fcγ RIII (CD16) and a ...potent in vitro antibody-dependent cellular cytotoxicity (ADCC). We examined several experimental designs for the biological anti-tumor activity of LFB-R603 as well as its sensitizing activity to apoptosis in resistant non-Hodgin's B-cell lymphoma (B-NHL) in comparison to rituximab. Treatment of the B-NHL cell line Ramos with LFB-R603 was not toxic at the concentrations used and induced cell aggregation following culture at 24 and 48 h similarly to rituximab. Hence, we hypothesized that LFB-R603 may signal the tumor cells and modify intracellular survival/anti-apoptotic pathways. Treatment of Ramos cells with LFB-R603 inhibited the constitutively active NF-κB survival pathway, followed by significant potentiation of TRAIL-mediated apoptosis. We examined the underlying molecular mechanism by which the LFB-R603-mediated NF-κB inhibition results in the reversal of tumor cell resistance to TRAIL. We hypothesized that downstream gene products regulated by NF-κB that are involved in the resistance may be involved in LFB-R603-mediated sensitization. We found that LFB-R603 inhibited NF-κB activation and the anti-apoptotic factor Snail and induced the pro-apoptotic factor RKIP. The direct roles of Snail and RKIP modulation by LFB-R603 in the reversal of B-NHL resistance to TRAIL were examined by knocking down Snail and overexpressing RKIP in Ramos cells, respectively. Both approaches increased significantly the cell sensitivity to TRAIL apoptosis. In addition to changes observed in the expression levels of Snail and RKIP, Ramos cells treated with LFB-R603 induced the expression of PTEN along with inhibition of the PI3K-AKT activated pathway. PTEN silencing in Ramos cells pretreated with LFB-R603 and TRAIL inhibited TRAIL apoptosis; thus, demonstrating that PTEN induction by LFB-R603 has a direct role in tumor cell sensitization to TRAIL apoptosis. Several of the findings obtained in the experimental designs with LFB-R603 were superior to those obtained with rituximab. Overall, the findings demonstrate that LFB-R603 interferes with the dysregulated NF-κB/Snail/RKIP/PTEN/AKT resistance circuitry in B-NHL cells. Further, the findings suggest that LFB-R603 may sensitize tumor cells to various apoptotic stimuli including cytotoxic ligands such as TRAIL and chemotherapeutic drugs.
PDF
