Rassegna della letteratura – marzo 2019

Terapia medica adiuvante e malattia metastatica

Díaz-Rodríguez E, Pérez-Peña J, Ríos-Luci C. et Al. – TRAIL receptor activation overcomes resistance to trastuzumab in HER2 positive breast cancer cells. Cancer Lett. 2019 Mar 27. pii: S0304-3835(19)30198-3. doi: 10.1016/j.canlet.2019.03.042.

The appearance of resistance to the anti-HER2 targeted drug trastuzumab constitutes, nowadays, an important challenge in the oncology clinic. To fight such resistance, we searched for potential vulnerabilities in cells resistant to that drug. To that end, we used cell lines primary resistant to trastuzumab, as well as cells made secondarily resistant to the drug upon continuous exposure. Using genomic and proteomic approaches, a deregulation in cell death pathways was identified in trastuzumab-resistant cells. More precisely, an increased response to the death factor TRAIL, caused by an increase in the cellular receptors for this factor, was observed. In parallel, a decrease in inhibitory components of the pathway was detected. This combination produces a more efficient assembly of the functional complex in the trastuzumab-resistant cells that translates in the observed increased response to TRAIL. Analysis of HER2 positive patient samples confirmed deregulation of this pathway in trastuzumab-resistant patients. Taken together our data identify a vulnerability of trastuzumab-resistant cells that could be used to design new targeted therapies in that context.

Mehta RS, Barlow WE, Albain KS et Al. – Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. – N Engl J Med. 2019 Mar 28;380(13):1226-1234. doi: 10.1056/NEJMoa1811714.

Background: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes

Methods: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.

Results: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.

Conclusion: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).

Bolam KA, Mijwel S, Rundqvist H, Wengström Y. – Two-year follow-up of the OptiTrain randomised controlled exercise trial. – Breast Cancer Res Treat. 2019 Mar 26. doi: 10.1007/s10549-019-05204-0.

Background: The aim of this study was to determine if there were any differences in health-related outcomes and physical activity (PA) between the two OptiTrain exercise groups and usual care (UC), 2 years post-baseline.

Methods: The OptiTrain study was a three-arm randomised controlled trial comparing 16 weeks of concurrent aerobic high-intensity interval training (HIIT) and progressive resistance exercise (RT-HIIT) or concurrent HIIT and continuous moderate-intensity aerobic exercise (AT-HIIT) to UC in 206 patients with breast cancer undergoing chemotherapy. Eligible participants were approached 2 years following baseline to assess cancer-related fatigue, quality of life, symptoms, muscle strength, cardiorespiratory fitness, body mass, PA, sedentary behaviour, and sick leave.

Results: The RT-HIIT group reported lower total cancer-related fatigue, (- 1.37, 95% CI - 2.70, - 0.04, ES = - 0.06) and cognitive cancer-related fatigue (- 1.47, 95% CI - 2.75, - 0.18, ES = - 0.28), and had higher lower limb muscle strength (12.09, 95% CI 3.77, 20.40, ES = 0.52) than UC at 2 years. The AT-HIIT group reported lower total symptoms (- 0.23, 95% CI - 0.42, - 0.03, ES = - 0.15), symptom burden (- 0.30, 95% CI - 0.60, - 0.01, ES = - 0.19), and body mass - 2.15 (- 3.71, - 0.60, ES = - 0.28) than UC at 2 years.

Conclusion: At 2 years, the exercise groups were generally experiencing positive differences in cancer-related fatigue (RT-HIIT), symptoms (AT-HIIT), and muscle strength (RT-HIIT) to UC. The findings provide novel evidence that being involved in an exercise program during chemotherapy can have long-term benefits for women with breast cancer, but that strategies are needed to create better pathways to support patients to maintain physical activity levels.

Antunovic L, De Sanctis R, Cozzi L et Al –PET/CT radiomics in breast cancer: promising tool for prediction of pathological response to neoadjuvant chemotherapy. – Eur J Nucl Med Mol Imaging. 2019 Mar 26. doi: 10.1007/s00259-019-04313-8

Background: To assess the role of radiomics parameters in predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer.

Methods: Seventy-nine patients who had undergone pretreatment staging 18F-FDG PET/CT and treatment with NAC between January 2010 and January 2018 were included in the study. Primary lesions on PET images were delineated, and extraction of first-, second-, and higher-order imaging features was performed using LIFEx software. The relationship between these parameters and pCR to NAC was analyzed by multiple logistic regression models.

Results: Nineteen patients (24%) had pCR to NAC. Different models were generated on complete information and imputed datasets, using univariable and multivariable logistic regression and least absolute shrinkage and selection operator (lasso) regression. All models could predict pCR to NAC, with area under the curve values ranging from 0.70 to 0.73. All models agreed that tumor molecular subtype is the primary predictor of the primary endpoint.

Conclusion: Our models predicted that patients with subtype 2 and subtype 3 (HER2+ and triple negative, respectively) are more likely to have a pCR to NAC than those with subtype 1 (luminal). The association between PET imaging features and pCR suggested that PET imaging features could be considered as potential predictors of pCR in locally advanced breast cancer patients.

Veeraraghavan J, De Angelis C, Mao R et Al. – A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. – Ann Oncol. 2019 Mar 23. pii: mdz076. doi: 10.1093/annonc/mdz076.

Background: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.

Methods: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab (with endocrine therapy for estrogen receptor (ER)+ tumors) in TBCRC006 were evaluated in a central laboratory for HER2 amplification by FISH (n=56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).

Results: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN < 10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥ 10 attained pCR (P=0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared to 1/23 (4%) with PI3K pathway alterations (P=0.0133). Seven of 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P=0.0031).

Conclusion: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Tarantino P, Curigliano G et Al, – Defining the immunogram of breast cancer: a focus on clinical trials. – Expert Opin Biol Ther. 2019 Mar 20:1-3. doi: 10.1080/14712598.2019.1598372.

In phase III ImPassion130 trial, the addition of immunotherapy to chemotherapy improved overall survival in metastatic triple-negative breast cancer patients. This benefit was significant only in patients harboring PD-L1-positive tumors, suggesting that stratification according to response biomarkers is needed to achieve consistent responses. Besides PD-L1 expression, a variety of potential biomarkers are under investigation for predicting immunotherapy efficacy in breast cancer, such as tumor-infiltrating lymphocytes, gene signatures, tumor mutational burden, microsatellite instability, and gut microbiome. Enriching future trials through these biomarkers could help identifying the population of responders, realizing what has been called precision immunotherapy.

Kashefi S, Omranipour R, Mahmoodzadeh H et Al. – A Randomized, Controlled, Phase II Clinical Trial of β-D-Mannuronic Acid (M2000) in Pre-surgical Breast Cancer Patients at Early Stage (T1-T2). – Clin Exp Pharmacol Physiol. 2019 Mar 18. doi: 10.1111/1440-1681.13086.

Following the potent efficacy of β-D-Mannuronic acid in breast cancer murine model, we evaluated the efficacy of this novel non-steroidal anti-inflammatory drug in breast cancer patients in this present clinical trial. The Study was an 8 weeks randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre-surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting-list for surgery and were allocated. β-D-Mannuronic was administrated at a dose of two capsules (1000 mg/day) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients’ well-being status was followed up on for safety. There were no statistically significant differences between treatment and non-treatment groups at baseline. β-D-Mannuronic acid therapy, from 20 patients, showed that in one patient (5%) tumor size was decreased; in five patients (25%) tumor growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non-treatment group. Evaluation of two tumor markers (carcinoembryonic antigen and cancer antigen 15-3) showed that there was no significant difference between before and after treatment. Although the use of some non-steroidal anti-inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β-D-Mannuronic acid during 8 weeks could show 30% therapeutic effects in pre-surgical breast cancer patients.