Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis

Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics

Clinical outcome data for symptomatic breast cancer: the breast cancer clinical outcome measures (BCCOM) project

Background: Data collection for screen-detected breast cancer in the UK is fully funded which has led to improvements in clinical practice. However data on symptomatic breast cancer are deficient, and the aim of this project was to monitor the current practice. Methods: A data set was designed together with surrogate outcome measures to reflect best practice. Data from cancer registries initially required the consent of clinicians, but in the third year anonymised data were available. Results: The quality of data improved but this varied by region and only a third of cases were validated by clinicians. Regional variations in mastectomy rates were identified and one third of patients who underwent conservative surgery for invasive breast cancer were not recorded as receiving radiotherapy. Conclusions: National data are essential to ensure that all patients receive appropriate treatment for breast cancer, but variations still exist in the UK and further improvement in data capture is required

A population based study of variations in operation rates for breast cancer, of comorbidity and prognosis at diagnosis: Failure to operate for early breast cancer in older women

Background Older women are less likely to have surgery for operable breast cancer. This population-based study examines operation rates by age and identifies groups which present with early or late disease. Methods 37 000 cancer registrations for 2007 were combined with Hospital Episode Statistics comorbidity data for England. Operation rates were examined by age, ethnicity, deprivation, comorbidity, screen-detection, tumour size, grade and nodal status. Early and late presentation were correlated with Nottingham Prognostic Index (NPI) groups and tumour size. Results The proportion of women not having surgery increased from 7–10% at ages 35–69 to 82% from age 90. From age 70, the proportion not having surgery rose by an average of 3.1% per year of age. Women with a Charlson Comorbidity Index score of ?1 (which increased with age), with tumours >50 mm or who were node positive, were less likely to have surgery. Although women aged 70–79 were more likely to have larger tumours, their tumours were also more likely to have an excellent or good NPI (p < 0.001). Good prognosis tumours were more likely to be screen-detected, and less likely in women aged 0–39, the deprived and certain ethnic groups (p < 0.02). Conclusions From age 70 there is an increasing failure to operate for breast cancer. Younger women and certain ethnic groups presented with more advanced tumours. Older women had larger tumours which were otherwise of good prognosis, and this would not account for the failure to operate which may in part be related to comorbidity in this age group

HER2 mediates PSMA/mGluR1-driven resistance to the DS-7423 dual PI3K/mTOR inhibitor in PTEN wild-type prostate cancer models

Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors

Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines

Breast cancer-specific mortality is static in older women despite having fallen in younger age groups, possibly due to lack of screening and differences in treatment. This study compared stage and treatment between two cohorts of postmenopausal women (55–69 vs 470 years) in a single cancer network over 6 months. A total of 378 patients were studied (470: N ¼ 167, 55–69 years: N ¼ 210). Older women presented with more advanced disease (470: metastatic/locally advanced 12%, 55–69 years: 3%, Po0.01). Those with operable cancer had a worse prognosis (Nottingham Prognostic Index (NPI) 470: median NPI 4.4, 55–69 years: 4.25, Po0.03). These stage differences were partially explained by higher screening rates in the younger cohort. Primary endocrine therapy was used in 42% of older patients compared with 3% in the younger group (Po0.001). Older women with cancers suitable for breast conservation were more likely to choose mastectomy (470: 57.5% mastectomy rate vs 55–69 years: 20.6%, Po0.01). Nodal surgery was less frequent in older patients (470: 6.7% no nodal surgery, 55–69 years: 0.5%, Po0.01) and was more likely to be inadequate (470: 10.7% o4 nodes excised, 55–69 years: 3.4%, Po0.02). In summary, older women presented with more advanced breast cancer, than younger postmenopausal women and were treated less comprehensively

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

This work was supported by Cancer Research UK (grants C1519/A6906 and C5255/A15935); by the King’s College London-UCL Comprehensive Cancer Imaging Centre (CRUK and EPSRC, grants C1519/A10331 and C1519/A16463), in association with the MRC and DoH (grant C1519/A10331); by the EU FP7 grants IMAGINT (EC grant: 259881); and by KCL Breast Cancer Now Unit funding (for F.F.-B.; grant KCL-Q2-Y5). J.G.C. is a Wellcome Trust Senior Research fellow (206346/Z/17/Z). The purchase of the siRNA library was possible thanks to a generous gift from Ms. Marianne B. Blake, who raised funds during the 2010 London Marathon through Dimbleby Cancer Care

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment