Targeted Therapies and Drug Resistance in Advanced Breast Cancer, Alternative Strategies and the Way beyond.

"Targeted therapy" or "precision medicine" is a therapeutic strategy launched over two decades ago. It relies on drugs that inhibit key molecular mechanisms/pathways or genetic/epigenetic alterations that promote different cancer hallmarks. Many clinical trials, sponsored by multinational drug companies, have been carried out. During this time, research has increasingly uncovered the complexity of advanced breast cancer disease. Despite high expectations, patients have seen limited benefits from these clinical trials. Commonly, only a minority of trials are successful, and the few approved drugs are costly. The spread of this expensive therapeutic strategy has constrained the resources available for alternative research. Meanwhile, due to the high cost/benefit ratio, other therapeutic strategies have been proposed by researchers over time, though they are often not pursued due to a focus on precision medicine. Notable among these are drug repurposing and counteracting micrometastatic disease. The former provides an obvious answer to expensive targeted therapies, while the latter represents a new field to which efforts have recently been devoted, offering a "way beyond" the current research.

Worldwide Survey of COVID-19-Associated Arrhythmias.

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Treatment of mild non-chemotherapy-induced iron deficiency anemia in cancer patients: comparison between oral ferrous bisglycinate chelate and ferrous sulfate.

In cancer patients mild-moderate non-chemotherapy-induced iron deficiency anemia (IDA) is usually treated with oral iron salts, mostly ferrous sulfate. In this study, we compare efficacy and toxicity of oral ferrous bisglycinate chelate and ferrous sulfate in cancer patients with mild IDA. Twenty-four patients operated on for solid tumors (10 breast, 12 colorectal, 2 gastric), aged 61±10 years (range 45-75), with non-chemotherapy-induced hemoglobin (Hb) values between 10 and 12 g/dL and ferritin lower than 30 ng/mL were randomized to receive oral ferrous bisglycinate chelate, 28 mg per day for 20 days, and then 14 mg per day for 40 days (12 patients) (A group) or oral ferrous sulphate, 105 mg per day for 60 days (12 patients) (B group). Values of hemoglobin and ferritin obtained at diagnosis, 1 and 2 months from the beginning of treatment were compared. Adverse events (AEs) related to the two treatments were recorded. In the 12 patients treated with ferrous bisglycinate chelate, basal hemoglobin and ferritin values (mean±SD) were 11.6±0.8 g/dL and 16.1±8.0 ng/mL. After 2 months of treatment, they were 13.0±1.4 g/dL and 33.8±22.0 ng/mL, respectively (P=0.0003 and P=0.020). In the group treated with ferrous sulphate, hemoglobin and ferritin mean values were 11.3±0.6 g/dL and 19.0±6.4 ng/mL basally, and 12.7±0.70 g/dL and 40.8±28.1 ng/mL (P<0.0001 and P=0.017) after 2 months of treatment. AEs occurred in six cases. In all these six cases, two (17%) treated with ferrous bisglycinate chelate and four (33%) with ferrous sulphate, toxicity was grade 1. In conclusion, these data suggest that ferrous bisglycinate chelate has similar efficacy and likely lower GI toxicity than ferrous sulphate given at the conventional dose of 105 mg per day for the same time.

An iron regulatory gene signature in breast cancer: more than a prognostic genetic profile?

Miller LD, Coffman LG, Chou JW et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 71(21), 6728-6737 (2011). In breast cancer, recent progress in technology has enabled us to define different prognostic genetic signatures. Based upon them, breast tumors have been grouped into the four principal categories: basal-like or triple-negative, erbB2-positive, normal-like, and luminal type (A and B); with luminal types sharing the expression of estrogen receptor- and/or progesterone receptor-related genes and, basal-like and erbB2-positive subgroups associated with worse prognosis. So far, Oncotype DX(®) (Genomic Health Inc., Redwood City, CA, USA), Mammaprint(®) (Agendia Inc, Huntington Beach, CA, USA), the Breast Cancer Index(®) (BCI, Biotheranostics, San Diego, CA, USA) and PAM50 (Expression Analysis Inc., Durham, NC, USA) are the only multigene assays that have been marketed in North America and Europe. However, any genetic signature assay still has to gain acceptance as a validated assay before introduction into current clinical practice. This study describes an iron regulatory gene signature (IRGS) in breast cancer associated with clinical outcome. Within the molecular luminal type, the IRGS provides prognostic information similar to Oncotype DX and gene sets selected to assess proliferation. In spite of this, it is relevant that two complementary pathways that are regulatory of iron metabolism - the iron export (Fp/HAMP) and the iron import (TFRC/HFE) gene dyads - were embedded in the IRGS gene set and were associated with clinical outcome as well. Differences in metabolic pathways between cancer and normal cells have been widely described, and potential applications for more refined therapy have been proposed by expanding genetic signature assessment technology to concomitant metabolic pathways investigation. Consistent with this, it is reasonable to imagine that the iron-export and the iron-import gene dyads will be considered potential targets for treatment of breast cancer patients expressing the IRGS genes.

Additional 5-FU-LV significantly increases survival in gastrointestinal cancer.

Metastatic colorectal and other locally advanced gastrointestinal (G.I.) cancers often recur after curative resection. Many mechanisms of tumor growth and/or immune escape by residual cancer cells may provoke tumor progression. Long-term, cytostatic action with repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles may interrupt or downregulate these mechanisms and favor the recovery and/or increase the immune system activity. Seventy patients were considered. An active prospective cohort including 21 patients (study group) was matched in a 1:1 ratio with a retrospective parallel control group of 21 patients. The study group received long-term repeated post-adjuvant administration of 5-FU-LV cycles, while the matched control group was conventionally treated. Statistical analysis was performed by Kaplan-Meier method and Cox's proportional hazard regression model. The five-year disease-free survival (DFS) was 77.0 + 10.1 % and 31.7 + 10.6 % (p = 0.001; hazard ratio (HR) 5.3, 95 % C.I.: 1.7-16.1, p = 0.003), while the five-year overall survival (OS) was 88.0 + 8.1 % and 37.0 + 10.7 % (p = 0.001; HR 8.9, 95 % C.I.: 2.0-39.9, p = 0.004) in the study group and in matched controls respectively. These findings suggest a relevant improvement in the outcome of this population by an intermittent and prolonged cytostatic effect with 5-FU-LV.

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect.

In metastatic colorectal and other locally advanced gastrointestinal cancers, the mechanisms of tumor growth and/or immune escape by residual cancer cells after curative resection often provoke tumor recurrence. Current adjuvant therapy is based on pharmacological administration up to 6-8 months after surgery. We hypothesized that the long-term, cytostatic action from repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles, as a result of the downregulation of the above-mentioned cellular mechanisms, could halt tumor progression. An active prospective cohort, including 19 patients (study group) at high risk of relapse, was considered. All patients received repeated post-adjuvant administration of 5-FU-LV cycles for up to 52-60 months following curative surgery (total cumulative dose of about 90 g and mean follow-up of 70.6 ± 49.7 months). The 5-year disease-free interval (DFS) and overall survival (OS) were 80.4 ± 10.2% and 87.1 ± 8.6%, respectively, which is very different from the recent literature that has reported 5-year DFS and OS values of 31.8% and 40.1%, respectively. These findings suggest that this new pharmacological approach based on the long-term maintenance of a cytostatic effect with 5-FU-LV can produce a relevant improvement in the outcome of this population.