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Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.

Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2−/− mice, an effect mimicked by CD8+ T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8+ T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression., Dissemination of tumor cells from the primary site is an early event. Here, the authors show that the early disseminated tumor cells are actively cleared by the host cytotoxic T lymphocytes induced by the primary tumor and that infiltration of granulocytic myeloid-derived suppressor cells counteracts such immune protection and allow metastasis development.

Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control and that this activity is likely due to effects on both BC and microenvironment cells.

In metastatic renal cell carcinoma (mRCC), the transition to the targeted therapy era has made available a variety of effective new agents, including vascular endothelial growth factor tyrosine kinase receptor (VEGF-TKR) inhibitors, such as sunitinib, pazopanib, sorafenib; anti-VEGF monoclonal antibody bevacizumab; and mTOR (mammalian target of rapamycin) inhibitors, everolimus and temsirolimus. A statistically significant improvement in progression-free survival (PFS) was obtained with each of these six biological drugs in well-conducted phase III trials, in comparison with either interferon alone (in the first-line setting) or placebo (in the second-line setting). As a consequence, all of these drugs have received regulatory approval in specific subsets of mRCC patients both in the US and in Europe (Gore and Larkin, 2011). Recently, VEGF-TKR inhibitor axitinib has proved to be a valuable second-line option in patients who have received targeted agents (Rini et al, 2011). With the rapidly growing number of biological drugs active in mRCC, the need to establish the optimal sequence of administration is becoming more and more compelling. In the first-line setting, no comparative phase III trial of targeted agents has been carried out (Gore and Larkin, 2011), although a number of indirect comparisons and economic evaluations involving sunitinib and bevacizumab are available. Sunitinib was associated to a prolonged PFS with respect to bevacizumab plus interferon in an indirect comparison analysis (Thompson Coon et al, 2009), but bevacizumab was more cost-effective than sunitinib in one study (Ravasio et al, 2011), although this finding was not replicated in another study (Benedict et al, 2011). Pazopanib has also recently emerged as an effective first-line treatment option (Gore and Larkin, 2011). Although cross-trial comparison is always challenging, pazopanib may be better tolerated than sunitinib, with a minor incidence of cardiovascular, endocrinologic and dermatologic adverse events, and it could be employed in selected patients (e.g., those with cardiovascular co-morbidities) (Di Lorenzo et al, 2011). Results from an ongoing head-to-head comparative phase III trial of first-line pazopanib vs sunitinib are eagerly awaited (COMPARZ trial, NCT 00720941). In the second-line setting, the only FDA- and EMA-approved drug after progression on VEGF-TK inhibitors is currently everolimus, which yielded a statistically meaningful PFS advantage (4.9 vs 1.9 months), with no difference in overall survival (OS), with respect to placebo, in a large phase III trial (Motzer et al, 2010). Progression-free survival obtained with everolimus was numerically superior to that obtained with second-line sorafenib in 52 patients with sunitinib-refractory mRCC by Di Lorenzo et al (2009). Importantly, although all of the patients enrolled in the Di Lorenzo trial had received a single agent for metastatic disease, 79% of patients in the RECORD-1 trial had received more than one medication for systemic disease at enrollement, including sunitinib, sorafenib or interferon. An indirect comparison analysis was performed by matching patients enrolled in these two trials for histology, prior treatment, and MSKCC risk score showed that everolimus was associated with a statistically significant improved median PFS (40.8 vs 17.7 weeks) and improved median OS (78 vs 32 weeks) with respect to sorafenib (Di Lorenzo et al, 2011). Interestingly, these data seem to be confirmed by another retrospective review of 108 mRCC patients treated with either the TKR inhibitor –TKR inhibitor sequence (46 patients), or with the TKI-EV sequence (62 patients). Although there was no difference in PFS, the estimated OS was statistically meaningfully longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p=0.03), but was only numerically longer at multivariable analysis (Busch et al, 2011). All of these data taken together support the notion that everolimus may be a better second-line choice than sorafenib. Furthermore, everolimus has been shown to preserve its efficacy in individuals who were intolerant to first-line TKR inhibitor, and may be particularly suitable for these patients (Bracarda et al, 2011). Treatment in the second-line setting has been further complicated by the recently published results obtained in the AXIS trial in patients pre-treated with one prior line of therapy, including interferon, bevacizumab or sunitinib, and randomized to either axitinib or sorafenib (Rini et al, 2011). Median PFS was 6.7 months with axitinib compared with 4.7 months with sorafenib (hazard ratio 0.665; 95% CI 0.544–0.812) in the whole sample population, but the PFS advantage was smaller in patients previously treated with sunitinib (4.8 vs 3.4 months; hazard ratio 0.741; 95% CI 0.573–0.958), which underlines the critical importance of previous therapy with targeted agents. Axitinib is likely to be soon approved for second-line use in mRCC and become an alternative to everolimus. The third-line setting remains largely unexplored, and all of the available evidence is provided by small, retrospective studies. In a recent case study published on this Journal, Grunwald et al (2011) presented retrospective data regarding treatment of 40 patients with mRCC, who received VEGF-directed targeted agents before and after the use of everolimus. Sunitinib, sorafenib and combination of bevacizumab and interferon were administered to 75%, 23% and 3% of patients, respectively, as a first-line treatment. All patients of the study sample received either second- or third-line everolimus and were subsequently treated with a VEGF-directed targeted drug, that is to say sunitinib, sorafenib, bevacizumab/interferon and dovitinib in 48%, 20%, 8% and 25% of patients, respectively. Collected data seemed to provide some evidence in favor of the efficacy of retreatment with a VEGF-directed targeted drug following everolimus, considering that median PFS with either a third- or forth-line VEGF-directed targeted agent was overall 5.5 months. Differently from the study by Grunwald et al, we conducted a retrospective study of patients with mRCC, who had undergone the exact sequence sunitinib-mTOR inhibitor-sorafenib (Di Lorenzo et al, 2010). Importantly, of 150 medical records considered, a substantial proportion (about 25%) received third-line treatment with sorafenib, which was associated to a median PFS of 4 months and an OS of 7 months. A possible biological explanation for this finding, which can be considered satisfactory in the third-line setting, is based on the existence of two mTOR complexes: mTORC1, which is formed by mTOR binding to the FK-binding protein and is targeted by everolimus, and mTORC2, which is not inhibited by everolimus and can be responsible for a compensatory increase of the hypoxia-inducible factor (Rini, 2010). Activation of the VEGF pathway can be consequently targeted by third-line use of TKr inhibitors. Resistance to VEGF-directed targeted agents has been simplified into two main mechanisms: one involving the potentiation of the VEGF axis and the other based on the activation of alternative pathways and growth factors (Powles et al, 2011). Interestingly, the former model can be employed to explain the second-line activity of axitinib, a potent and selective (unlike sunitinib, pazopanib and sorafenib) inhibitor of VEGF-r. In fact, VEGFr may still be activated during VEGF-directed therapies via a number of mechanisms, such as increased VEGF production or receptor gene mutation, and the use of a more potent VEGFr inhibitor can be clinically meaningful. On the other hand, a number of separate pathways have been identified as possibly mediating acquired resistance to VEGF-directed biological agents. Activation of these pathways can stimulate angiogenesis both directly and indirectly via a number of proteins, such as fibroblast growth factor, ephrin and angiopoietin family proteins, interleukin-8 and PlGF. In this regard, it must be noted that activity of combination of synergism of bevacizumab and interferon may be explained by the bFGF-inhibiting activity of interferon. Furthermore, preliminary evidence suggests efficacy of an angiopoietin-2 inhibitor, AMG386, which is currently being investigated in two ongoing phase II trials in combination with either sunitinib or sorafenib (Rini et al, 2011). In conclusion, in patients at good- and intermediate-prognosis with clear cell mRCC sunitinib presently appears the best first-line choice, with pazopanib as a valuable alternative in selected populations. In this regard, it must be kept in mind that most of the available evidence in the second-line setting was obtained in sunitinib-pretreated patients, so efficacy data in patients treated with first-line pazopanib are lacking. Both axitinib and everolimus may be employed interchangeably as second- and third-line therapies. Everolimus may be used after axitinib, in view of the fact that the RECORD-1 trial also enrolled patients who had received two targeted therapies, and that the number of prior agents employed was not predictive of PFS. On the other hand, axitinib effectiveness may be enhanced after use of everolimus, for the reasons explained before. Temsirolimus is the only recommended treatment for patients with non-clear cell histology and those at poor prognosis, for whom a TKI-based second-line treatment is a reasonable option. Additional trials are eagerly awaited, in order to provide evidence regarding the best choice and sequence of administration of targeted agents in mRCC.