Rassegna della letteratura – maggio 2019

Biologia, genetica, laboratorio e anatomia patologica

Tajbakhsh A, Rivandi M, Abedini S et AL – Regulators and mechanisms of anoikis in triple-negative breast cancer (TNBC): A review. – Crit Rev Oncol Hematol. 2019 May 18;140:17-27.

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.

Tong YW, Wang G, Wu JY et Al. – Insulin-like growth factor-1, metabolic abnormalities, and pathological complete remission rate in HER2-positive breast cancer patients receiving neoadjuvant therapy. – Onco Targets Ther. 2019 May 21;12:3977-3989.

Purpose: HER2-positive breast cancer (BC) achieving pathological complete remission (pCR) after neoadjuvant therapy (NAT) had a superior disease outcome. Dysmetabolism and stimulation of insulin-like growth factor 1 (IGF-1)-axis would increase BC risk, but we are lacking data for their association with pCR in HER2-positive+ BC. We aim to evaluate the pCR predictive value of above factors in HER2-positive BC patients receiving NAT. Patients and methods: HER2-positive BC patients receiving NAT ± trastuzumab were retrospectively included between January 2013 and December 2016. Data were compared between baseline at biopsy and surgery. Median value of IGF-1 expression was used as cutoff value to classify patients into low or high group. pCR was defined as no residual invasive carcinoma in breast and axilla. Results: Overall, 101 patients were included. Metabolic syndrome was diagnosed in 29 (28.71%) with an average of 1.71±1.51 metabolic disorders at baseline, significantly increased after NAT (2.12±1.54, P<0.001). Lipid metabolism factors, including triglycerides, TC, HDL-C and LDL-C significantly worsened after NAT (all P<0.05). Average post-NAT IGF-1 was 196.14±86.03 ng/mL (vs preNAT 186.41±75.03 ng/mL, P=0.182). pCR was achieved in 29 (28.71%) patients. pCR rate was 40.00% and 17.65% for those with low or high preIGF-1 level (P=0.013). Multivariate analysis found that low IGF-1 expression, but not any other metabolic variable, was significantly associated with higher pCR rate in whole population (OR: 3.83, 95%CI: 1.32-11.11, P=0.014) or in patients receiving NAT + trastuzumab (OR: 3.93, 95%CI: 1.13-13.63, P=0.031). With a median follow-up of 29.03 (range: 10.42-56.98) months, IGF-1 level was not associated with overall survival (P=0.328) or disease-free survival (P=0.288). Conclusion: Low IGF-1 level was related with higher pCR rate in HER2-positive BC patients receiving NAT, which deserves further clinical evaluation

Hopkins AM, Rowland A, Logan JM et AL – Primary predictors of survival outcomes for HER2-positive advanced breast cancer patients initiating ado-trastuzumab emtansine. – Breast. 2019 May 11;46:90-94.

Background: Common therapies for HER2-positive advanced breast cancer (ABC) are associated with heterogeneity in prognosis and treatment benefit. Prognostic models of survival outcomes with ado-trastuzumab-emtansine (T-DM1) have not been evaluated.

Methods: A pre-treatment prognostic model for overall survival (OS) and progression-free survival (PFS) based on clinicopathological factors was developed for HER2-positive ABC patients initiating second-line and later T-DM1 using data from the randomised clinical trials EMILIA and TH3RESA (n = 893). Pre-treatment prognostic groups were identified via recursive partitioning analysis.

Results: The most significant OS/PFS pre-treatment risk predictors were metastatic sites count (≤2 versus > 2) and ECOG performance-status (0 versus ≥ 1) (P < 0.05). Based on these two factors, patients can be characterised as one of three prognostic groups (good = 0 factors; intermediate = 1 factor; poor = 2 factors). The prognostic groups were identified as significantly associated with OS (P < 0.001) and PFS (P < 0.001). Median OS for the good, intermediate and poor prognostic groups were 40 (95%CI: 36-48), 25 (23-30) and 16 (14-19) months, respectively, and median PFS was 12 (10-15), 8 (7-9) and 6 (4-7) months

Conclusions: Pre-treatment prognostic groups with significant differences in OS and PFS for HER2-positive ABC patients initiating second-line and later T-DM1 were identified. For HER2-positive ABC patients considering initiating second-line and later T-DM1, the prognostic groups enable more personalized expectations of disease control, survival and absolute treatment benefit.

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Huang Y, Fang J, Lu W, Wang Z et AL – A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling. Cell Chem Biol. 2019 May 30. pii: S2451-9456(19)30173-4.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease that lacks clinically actionable genetic alterations that limit targeted therapies. Here we explore a systems pharmacology approach that integrates drug-target networks and large-scale genomic profiles of TNBC and identify wogonoside, one of the major active flavonoids, as a potent angiogenesis inhibitor. We validate that wogonoside attenuates cell migration, tube formation, and rat aorta microvessel outgrowth, and reduces formation of blood vessels in chicken chorioallantoic membrane and TNBC cell-induced Matrigel plugs. In addition, wogonoside inhibits growth and angiogenesis in TNBC cell xenograft models. This network-based approach predicts, and we empirically validate, wogonoside’s antiangiogenic effects resulting from vascular endothelial growth factor secretion. Mechanistically, wogonoside inhibits Gli1 nuclear translocation and transcriptional activities associated with Hedgehog signaling, by promoting Smoothened degradation in a proteasome-dependent mechanism. This study offers a powerful, integrated, systems pharmacology-based strategy for oncological drug discovery and identifies wogonoside as a potential TNBC angiogenesis inhibitor

Alwhaibi M, Lilly CL, Hazard H et AL – Breast Cancer Survivors’ Perceptions of Prevention versus Control of Future Cancer Recurrence. – Int J Breast Cancer. 2019 May 2;2019:2652180

Background: The Institute of Medicine has established Survivorship Care Planning as a critical component of cancer care to ensure that cancer survivors receive the appropriate follow-up care in a timely manner and support cancer survivors in dealing with the risk of recurrence, yet little is known about how cancer survivors think about preventing or controlling future cancer recurrence. This study sought to assess breast cancer women’s perceived prevention and perceived control of future cancer recurrence.

Methods: Women with a history of breast cancer (n=114) were surveyed, and data were analyzed using concurrent mixed methods. Binary logistic regression models examined predictors of perceived prevention and perceived control of cancer recurrence.

Results: Most women perceived that they could control cancer recurrence (89%); few (30%) perceived that they could prevent cancer recurrence. Women reported components of the timeline (e.g., early diagnosis), identity (e.g., cancer in body), causes (e.g., hereditary), consequences (e.g., witness success), and cure/control (e.g., exercise) or lack of cure/control. Women who reported lack of control were less likely to perceive that they could control cancer recurrence. Women who reported causes were less likely to perceive that they could prevent or control cancer recurrence.

Conclusions: Women’s perceptions about the prevention and control of cancer recurrence are important and different factors in the minds of women with breast cancer. Most women believed they could control cancer recurrence; however, few believed they could prevent cancer recurrence. Interventions to focus on control of cancer recurrence, focusing on evidence-based clinical and lifestyle interventions, are needed.