Rassegna della letteratura – maggio 2019

Terapia medica adiuvante e malattia metastatica

Basu A, Ramamoorthi G, Jia Y et AL. – Immunotherapy in breast cancer: Current status and future directions. – Adv Cancer Res. 2019;143:295-349.

Breast cancer, one of the leading causes of death in women in the United States, challenges therapeutic success in patients due to tumor heterogeneity, treatment resistance, metastasis and disease recurrence. Knowledge of immune system involvement in normal breast development and breast cancer has led to extensive research into the immune landscape of breast cancer and multiple immunotherapy clinical trials in breast cancer patients. However, poor immunogenicity and T-cell infiltration along with heightened immunosuppression in the tumor microenvironment have been identified as potential challenges to the success of immunotherapy in breast cancer. Oncodrivers, owing to their enhanced expression and stimulation of tumor cell proliferation and survival, present an excellent choice for targeted immunotherapy development in breast cancer. Loss of anti-tumor immune response specific to oncodrivers has been reported in breast cancer patients as well. Dendritic cell vaccines have been tested for their efficacy in generating anti-tumor T-cell response against specific tumor-associated antigens and oncodrivers and have shown improved survival outcome in patients. Here, we review the current status of immunotherapy in breast cancer, focusing on dendritic cell vaccines and their therapeutic application in breast cancer. We further discuss future directions of breast cancer immunotherapy and potential combination strategies involving dendritic cell vaccines and existing chemotherapeutics for improved efficacy and better survival outcome in breast cancer.

Bayraktar S, Batoo S, Okuno S – Immunotherapy in breast cancer. – J Carcinog. 2019 May 23;18:2.

The idea of using the immune system to fight cancer is over 100 years old. A new molecular approach led to a better understanding of the immune system. Checkpoint regulation, understanding the roles of Tregs, Th1, and Th2, development of Chimeric antigen receptor (CAR)-T cells, as well as regulation of dendritic cells and macrophages, are just a few examples of our understating that has also led to the discovery of immune checkpoint inhibitors (ICIs) and modulators. This led the Nobel Prize committee in 2018, to award Dr. James P. Allison the Nobel Prize in medicine for the discovery of Cytotoxic T-lymphocyte-associated antigen-4, and Dr. Tasuku Honjo for the discovery of programmed cell death-1 (PD-1)/PD-1-ligand (PDL-1). Several ICIs are already approved by the regulatory authorities, and many more are currently used in studies of several solid tumors and hematologic malignancies. Positive studies have led to the US Food and Drug Administration (FDA) and European Medicines Agency approval of a number of these compounds, but none to date are approved in breast cancer (BC). Moreover, PD-1/PDL-1, MSI high (and dMMR), and tumor mutational burden are the currently “best” predictive markers for benefit from immunotherapy. BCs have some of these markers positive only in subsets but less frequently expressed than most other solid tumors, for example, malignant melanoma or non-small cell lung cancer. To improve the potential efficacy of ICI in BC, the addition of chemotherapy was one of the strategies. Many early and large clinical trials in all phases are underway in BC. We will discuss the role of immune system in BC editing, and the potential impact of immunotherapy in BC outcomes.

Ruíz-Borrego M, Guerrero-Zotano A, Bermejo B et AL – Phase III evaluating the addition of fulvestrant (F) to anastrozole (A) as adjuvant therapy in postmenopausal women with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (EBC): results from the GEICAM/2006-10 study. – Breast Cancer Res Treat. 2019 May 31

Background GEICAM/2006-10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy.

Methods: Multicenter, open label, phase III study. HR+/HER2- EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1-3/≥ 4); HR status (both positive/one positive) and site. disease-free survival (DFS). Planned sample size: 2852 patients.

Results: The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58-1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%).

Conclusions: The GEICAM/2006-10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.

Roberts R, Hanna L, Borley A et AL – Epirubicin chemotherapy in women with breast cancer: Alternating arms for intravenous administration to reduce chemical phlebitis. – Eur J Cancer Care (Engl). 2019 May 31:e13114

Background: To establish whether using alternating arms for peripheral intravenous epirubicin administration affects the severity or duration of epirubicin-induced phlebitis.

Methods: An observational study of women with breast cancer (n = 237) in a UK Cancer Centre. Data were analysed after receiving three treatment cycles according to the arm used for epirubicin administration: same, alternating or mixed arm (two consecutive cycles in one arm and one in the alternate arm). Phlebitis severity was graded by clinical staff after each treatment; participants also self-reported symptoms during treatment and for up to 6 months after.

Results: The alternating arm group experienced significantly less severe symptoms than the other arm use groups, 6% (4 of 64) compared with 34% (p < 0.001, odds ratio: 0.13 (95% CI: 0.043-0.38) alternating arm compared with same arm group). The alternating arm group reported less pain (p = 0.013), lower overall impact (p = 0.009), lower effect on function (p = 0.032) and shorter duration of symptoms (p = 0.001) than the other arm use groups.

Conclusions: Using alternating arms for peripheral administration of epirubicin significantly reduces the severity and duration of chemical phlebitis and is recommended to improve patient experience and reduce the need for central venous access devices.