Akt2: a role in breast cancer metastasis.

Metastasis in breast cancer significantly increases morbidity and mortality. The 5-year survival rate reduces from 90% for localised disease to about 20% once metastasis has taken place. The phosphoinositide 3-kinase/Akt signalling pathway has an important role in cell motility, invasion and metastasis. However, the precise contribution of the Akt kinase family members, Akt1, Akt2 and Akt3, in mediating these processes is unclear. The possibility that they have distinct functions in tumour progression is particularly interesting

Efficacy and Safety of an Attenuated-Dose Sunitinib Regimen in Metastatic Renal Cell Carcinoma: Results From a Prospective Registry in Singapore

The use of sunitinib at conventional doses (50 mg/d, 4 weeks of treatment, then 2 weeks of no treatment) in Asian patients is associated with high toxicities. We evaluated 160 patients with metastatic renal cell carcinoma in Singapore, of which 127 were treated with an attenuated-dose regimen (37.5 mg/d, 4 weeks of treatment, then 2 weeks of no treatment). We observed comparable progression-free survival and overall survival between 2 regimens, and significant reduction in toxicities for patients treated with the attenuated regimen. The use of sunitinib at conventional doses (50 mg/d, 6-week cycles: 4 weeks of treatment, then 2 weeks of no treatment) in Asian patients with metastatic renal cell carcinoma (mRCC) is associated with high real-world toxicities. Patients with mRCC treated with sunitinib between 2005 and 2012 at 4 centers representing a near-national cohort (n = 160) in Singapore were evaluated. One hundred twenty-seven consecutive patients in 1 center were treated with a novel attenuated-dose sunitinib regimen (37.5 mg/d, 6-week cycle: 4 weeks of treatment, then 2 weeks of no treatment) with outcomes captured in a prospective registry. Efficacy and safety outcomes of these patients were compared against those who received sunitinib at conventional dosing (n = 33) at all 4 centers. Statistical modeling was adjusted for baseline prognostic criteria and therapy line where possible. Overall survival from treatment initiation (OSinitiation), overall survival from the first documented metastasis (OStotal), and progression-free survival (PFS) were similar for patients who received first-line sunitinib for conventional relative to attenuated dose regimens (OSinitiation: 18.3 vs. 16.5 months, respectively; P = .54; OStotal: 27.4 vs. 21.8 months, respectively; P = .45; PFS: 6.7 vs. 7.9 months, respectively; P = .64), similar to real-world outcomes in Western studies. A marked lower rate of severe toxicities, dose delays, and reductions were observed with the attenuated dose regimen, with 75/127 (59%), rather than 28/33 (85%) for the conventional dose arm who experienced Grade ≥ 3 toxicities (P = .0088); 31/127 (24%) rather than 19/33 (58%) who experienced dose delays (P = .0004); and 44/127 (35%) rather than 23/33 (70%) who experienced dose reduction (P = .0005) during their course of treatment. An attenuated dose regimen of sunitinib yielded comparable real-world efficacy outcomes, with considerable reduction in toxicities as documented in a prospective registry

Survival curves.

<p>(A) Patients grouped according to the <i>ABCB1 3435C/T</i>, <i>1236C/T</i>, <i>2677G/T</i> haplotype; median PFS was 2.4 months for homozygous carriers of the <i>TTT</i> haplotype and 8.4 months for other cases (<i>P</i> = 0.001). (B) Patients grouped according to the <i>ABCB1 3435C/T</i>, <i>1236C/T</i>, <i>2677G/TA</i> haplotype; median OS was 4.6 months for homozygous carriers of the <i>TTT</i> haplotype and 19.6 months for other cases (<i>P</i> = 0.005).</p

Polymorphisms genotyped and allele frequencies.

<p>^a Patients successfully genotyped.</p><p>^b Includes 34 <i>GT</i> and 10 <i>AG</i> individuals.</p><p>^c Includes 2 <i>AA</i>, 12 <i>AT</i> and 13 <i>TT</i> individuals.</p><p>^d A 2,903-bp deletion polymorphism in intron 2 of <i>BIM</i> previously associated with resistance to tyrosine kinase inhibitors [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134102#pone.0134102.ref028" target="_blank">28</a>]. As we were unable to genotype formalin-fixed tissues with the current method, only 45 patients were typed.</p><p>^e Variant allele frequencies.</p><p>Polymorphisms genotyped and allele frequencies.</p

Association of <i>ABCB1</i> and <i>FLT3</i> Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma

<div><p>Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in <i>FLT3</i>, <i>ABCB1</i>, <i>VEGFR2</i>, <i>ABCG2</i> and <i>BIM</i> with patient toxicities, response, and survival. We observed a stronger association of <i>FLT3 738T</i> genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; <i>P</i>=0.03). We observed significant associations of <i>FLT3 738T</i> (OR=2.7), <i>ABCB1 1236T</i> (OR=0.3), <i>ABCB1 3435T</i> (OR=0.1), <i>ABCB1 2677T</i> (OR=0.4), <i>ABCG2 421A</i> (OR=0.3) alleles and <i>ABCB1 3435</i>, <i>1236</i>, <i>2677 TTT</i> haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, <i>P</i>=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, <i>P</i>=0.001; overall: HR=5.0, <i>P</i>=0.005) were associated with the <i>ABCB1 3435</i>, <i>1236</i>, <i>2677 TTT</i> haplotype. In conclusion, <i>ABCB1</i> and <i>FLT3</i> polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between <i>FLT3 738T</i> and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.</p></div

Patient demographics and baseline characteristics (n = 97).

<p>Patient demographics and baseline characteristics (n = 97).</p