Attualità in Senologia

Rassegna della letteratura: gennaio – marzo 2019
Oncologia medica e terapie per il controllo sistemico

Xu D,  Li X, Mao Z et Al – Addition of Capecitabine in Breast Cancer First-line Chemotherapy Improves Survival of Breast Cancer Patients. – J Cancer. 2019 Jan 1;10(2):418-429. doi: 10.7150/jca.29739. eCollection 2019

Background: Capecitabine is an antimetabolic fluoropyrimidine deoxynucleoside carbamate drug that can be converted to 5-FU in vivo. Currently, the role of capecitabine in the treatment of advanced breast cancer has been recognized. Also, Several meta-analyses have elucidated the role of capecitabine in the treatment of breast cancer, indicating that taxane-based regimen with capecitabine may be an effective, convenient, and well tolerated regimen in patients with early breast cancer. However, the correlation between capecitabine-based combination first-line chemotherapy and breast cancer survival remains unclear. Here, we present a meta-analysis to systematically evaluate the safety and effectiveness of capecitabine-based combination with first-line chemotherapy treatment in breast cancer.

Methods: We searched Pubmed, Embase, and Medline for relevant studies evaluating pooled estimated hazard ratios of capecitabine in breast cancerpatients with the eligible criteria up to June 2018. Fixed and random-effect meta-analyses were conducted based on heterogeneity of included studies.

Results: Overall, 10 articles with 12,872 patients were included in the meta-analysis. Capecitabine-based combination first-line chemotherapy compared with non-combination had significant impacts on disease-free survival (HR = 0.84, 95% CI: 0.76-0.93; P = 0.000) and overall survival (HR = 0.84, 95% CI: 0.74-0.94; P = 0.001). Also, according to the 3 articles concerning neoadjuvant chemotherapy which included 2534 participants, we found that the addition of capecitabine significantly improved OS (HR = 0.89, 95% CI: 0.63-0.86; P = 0.011). In the subgroup analysis, TNBC patients got significant benefits with the addition of capecitabine in DFS (HR = 0.77, 95% CI: 0.65-0.92; P = 0.004) and OS (HR = 0.65, 95% CI: 0.51-0.81; P = 0.000). ER negative patients got significant benefits in OS (HR = 0.73, 95% CI: 0.57-0.93; P = 0.012). The association of DFS with the addition of capecitabine in Her- patients (HR = 0.84, 95% CI: 0.71-0.99; P = 0.005) was significant, as was OS (HR = 0.82, 95% CI: 0.70-0.95; P = 0.009),. Meanwhile, patients receiving capecitabine-based combination first-line chemotherapy underwent less adverse effects especially the grade 3/4 leucopenia than patients with non-combination therapy (RR=0.72 95% CI: 0.59-0.86; P = 0.000).

Conclusion: Capecitabine combined with first-line chemotherapy in the treatment of breast cancer is an effective and safe treatment option and is worthy of clinical application to improve survival of breast cancer patients. In the future, we can continue to carry out relevant researches to explore the upmost appropriate dose of capecitabine for breast cancer.

Perez JL, Ozpinar A et Al. – Salvage Stereotactic Radiosurgery in Breast Cancer Patients With Multiple Brain Metastases. – World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30206-2.

Background: The overall survival rates for breast cancer are increasing due to controlled brain disease and improved systemic treatments. This study examined neurological outcomes, tumor control, and survival data in breast cancer patients with multiple brain metastases, and who required salvage stereotactic radiosurgery (SRS) for recurrent breast cancer brain metastases.

Methods: The study included 231 patients with a primary diagnosis of breast cancer who underwent SRS for greater than one brain metastases from May 1993 and July 2007. Survival analyses via univariate and multivariate Cox regression demonstrated interactions between survival and predictor values including KPS, RPA Class, number of brain metastases, whole brain radiotherapy (WBRT), immunotherapy, and chemotherapy.

Results: Of the 231 patients, the survival rate was 53% at 1 year and 26% at 5 years from initial SRS. Controlled systemic disease, adjuvant chemotherapy, and RPA Class II were significant predictors of increased survival, while WBRT was a significant predictor of decreased survival. The median survival in patients who received WBRT after SRS was 11 months versus 23 months in those who did not. The local tumor control rate at initial follow-up was 95%. Of these, 40% of patients underwent additional brain SRS. Following salvage SRS, 8% of patients developed symptomatic adverse radiation events (ARE), however, the development of symptomatic ARE had no effect on patient survival.

Conclusion: This report indicated that both initial and salvage SRS procedures in breast cancer patients with multiple brain metastases is effective for local control of intracranial disease, while minimizing adverse radiation effects.

Montemurro F, Ellis P et Al. – Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1. – Eur J Cancer. 2019 Jan 29;109:92-102.

Background: Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC).

Methods: KAMILLA is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression.

Results: Among 2002 treated patients, median age was 55 years (range, 26-88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0-7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5-28.7). With increasing lines of prior advanced therapy (0-1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively.

Conclusion: KAMILLA is the largest cohort of T-DM1-treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC.

Kim R, Kawai A et Al. – A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients. – Cancer Immunol Immunother. 2019 Jan 23. doi: 10.1007/s00262-019-02305-z.

Tumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II-IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-generation sequencing. Following NAC, pNK cell activity was increased in 24/39 patients but decreased in 15/39 patients. Increased pNK cell activity following preoperative chemotherapy was associated significantly with the disappearance of axillary lymph node metastasis (Ax+; p = 0.0235). Increased pNK cell activity remained significantly associated with the disappearance of Ax+ in multivariate logistic regression analysis (OR 5.41, 95% CI 1.19-24.52, p = 0.0283). A Grade 2 or higher effect of NAC was associated with high pre-NAC cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels (p = 0.0281) and elevated post-NAC NK (p = 0.0005) cells and transforming growth factor-beta (TGF-β; p = 0.0350) levels. The disappearance of Ax+ was associated with high pre-NAC CTLA-4 levels (p = 0.0278) and elevated CD4 levels after NAC (p = 0.0250). The systemic activation of pNK cells after NAC may improve metastatic tumor elimination in patients with breast cancer owing to a release from local immunosuppression, and immune activation in the tumor microenvironment.

Camilio KA, Wang MY et Al. – Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model. – Breast Cancer Res. 2019 Jan 22;21(1):9. doi: 10.1186/s13058-018-1092-x.

Background: Immunochemotherapy, the combined use of immunotherapy and chemotherapy, has demonstrated great promise in several cancers. LTX-315 is an oncolytic peptide with potent immunomodulatory properties designed for the local treatment of solid tumors. By inducing rapid immunogenic cell death through the release of danger-associated molecular pattern molecules (DAMPs), LTX-315 is capable of reshaping the tumor microenvironment, turning “cold” tumors “hot” through a significant increase in tumor-infiltrating lymphocytes.

Methods: We investigated the potential of LTX-315 to be used in combination with standard-of-care chemotherapy (doxorubicin, brand name CAELYX®) against triple-negative breast cancer in an orthotopic 4 T1 mammary fat pad model. Tumor growth curves were compared using one-way ANOVA analysis of variance and Tukey’s multiple comparisons test, and animal survival curves were compared using the log-rank (Mantel-Cox) test. We considered p values ≤0.05 to indicate statistical significance

Results: We found that LTX-315 displayed a strong additive antitumoral effect when used in combination with CAELYX®, and induced immune-mediated changes in the tumor microenvironment, followed by complete regression in the majority of animals treated. Furthermore, imaging techniques and histological examination showed that the combination induced strong local necrosis, followed by an increase in the infiltration of CD4+ and CD8+ immune cells into the tumor parenchymal tissue.

Conclusion: Our data demonstrate that LTX-315 is a promising combination partner with CAELYX® for the treatment of triple-negative breast cancer.