Rassegna della letteratura – aprile 2019

Terapia medica adiuvante e malattia metastatica

Adamson K, Chavez-MacGregor M et Al.- Neoadjuvant Chemotherapy does not Increase Complications in Oncoplastic Breast-Conserving Surgery. – Ann Surg Oncol. 2019 Apr 29. doi: 10.1245/s10434-

Background: Oncoplastic breast-conserving surgery (OBCS) broadens the indications for breast conservation. Neoadjuvant systemic chemotherapy (NAC) is used increasingly in the treatment of patients with early-stage and locally advanced breast cancer. This study aimed to evaluate the outcomes for patients who received NAC followed by OBCS

Methods: A retrospective chart review was performed for all patients who underwent OBCS involving the mastopexy/breast-reduction technique, including synchronous mastopexy/breast reduction for symmetry, at the University of Texas MD Anderson Cancer Center between January 2010 and January 2016. Patients who had received NAC were compared with those who had undergone surgery first. Demographic, treatment, and outcomes data were collected.

Results: The study included 429 patients, corresponding to 713 breasts. Of these patients, 122, corresponding to 199 breasts, received NAC. The patients who received NAC were younger (p < 0.001) and had a more advanced cancer stage (p < 0.001). The overall complication rate per patient was 25.9%, with major complications occurring in 9.1% of the patients. After adjustment for risk factors, NAC was not shown to be associated with an increased risk of complications or delayed adjuvant radiation therapy (p = 0.37), irrespective of the chemotherapy regimen used or whether the interval between NAC and surgery was 4 weeks or longer.

Conclusions: In a high-volume center, OBCS can be performed safely for carefully selected patients after NAC without an increased risk of complications or delayed adjuvant radiation therapy. An interval of at least 4 weeks between completion of NAC and surgery can be regarded as safe irrespective of the chemotherapy regimen used.

Schmidt ME, Scherer S et Al – Return to work after breast cancer: The role of treatment-related side effects and potential impact on quality of life.Eur J Cancer Care (Engl). 2019 Apr 29:e13051. doi: 10.1111/ecc.13051.

Background: For breast cancer survivors return to work (RTW) is important from an economic, societal and personal perspective. Thus, we investigated the impact of side effects and other factors on RTW. Five years post-diagnosis 135 disease-free breast cancer survivors below retirement age who were employed pre-diagnosis recorded their current and previous working status and reasons for impaired RTW. Patient-reported outcomes were prospectively reported over the cancer continuum. One year post-surgery 57% of survivors worked the same and 22% with reduced working time compared to pre-diagnosis. Logistic regression revealed significant associations of depressive symptoms, arm morbidity, lower education and younger age with impaired RTW after 1 year, and persisting physical fatigue and living with partner with impaired RTW after 5 years. Major self-reported reasons included fatigue and cognitive problems. Temporal patterns of general quality of life (QoL), physical, cognitive and role function, and financial problems were significantly worse among women with no RTW compared to those working again. In conclusion, cessation of work after breast cancer seems associated with worse QoL. Fatigue, psychological and cognitive problems as well as arm morbidity seemed to hinder RTW. Thus, a better management of these problems might help women to stay in working life.

Ciruelos E, Apellániz-Ruiz M et Al – A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer. Oncologist. 2019 Apr 25. pii: theoncologist.2017-0664. doi: 10.1634/theoncologist.

Background: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity.

Methods: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated.

Results: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients’ experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy.

Conclusions: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

Chao X, Chen K et Al. – Adjuvant radiotherapy and chemotherapy for patients with breast phyllodes tumors: a systematic review and meta-analysis. – BMC Cancer. 2019 Apr 23;19(1):372. doi: 10.1186/s12885-

Background: As the efficacy of radiotherapy and chemotherapy for treatment of phyllodes tumors (PTs) remains unclear, this study aimed to review all available data and evaluate the roles of radiotherapy and chemotherapy in PT treatment

Methods: We performed a comprehensive search of databases, including PubMed, Web of Science and the Cochrane Library. The outcomes of interest included the local recurrence (LR) rate, metastasis rate, disease-free survival rate and overall survival rate.

Results: Seventeen studies enrolling 696 patients were included in this random effect meta-analysis. Subgroup analysis and meta-regression were also conducted to determine study heterogeneity. A pooled local recurrence rate of 8% (95% CI: 1-22%) was observed with a statistical heterogeneity of I2 = 86.6% (p < 0.01) for radiotherapy. This was lower than the recurrence rate of 12% for simple surgical treatment (95% CI: 7-18%). Meta-regression analysis found that surgical margin status was the main source of heterogeneity (p = 0.04). The metastasis rate of 4% (95% CI: 0-11%) for patients receiving radiotherapy without significant heterogeneity was also lower than the rate for the simple surgery group (8, 95% CI: 3-15%). The available data for chemotherapy were too limited to support meta-analysis. Accordingly, we offer a pure review of these data.

Conclusions: Our findings suggest that radiotherapy is effective in achieving local disease control and preventing metastasis.

Li J, Wang Z et Al – Fulvestrant in the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: A review. – Cancer Med. 2019 Apr 19. doi: 10.1002/cam4.2095.

Nearly 75% of breast cancers are hormone receptor-positive (HR+) and human epidermal growth factor receptor type 2-negative (HER2-), making endocrine therapy the mainstay of treatment for HR+ and HER2- combination. Although endocrine therapy, such as therapy with fulvestrant, is widely used in the clinic, endocrine resistance (primary or secondary) is inevitable and poses a serious clinical concern. However, the therapeutic landscape of HR+/HER2- breast cancer is rapidly changing and evolving. In recent years, molecular insights into the genome of HR+/HER2- breast cancer have helped to identify promising targets, such as alterations in signaling pathways [phosphatidylinositide 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR)], dysregulation of the cell cycle (CDK4/6), and identification of new ESR1 mutations. These insights have led to the development of newer targeted therapies, which aims at significantly improving survival in these patients. This review summarizes the role and rationale of fulvestrant when used as a monotherapy or in combination with targeted therapies in patients with HR+/HER2- advanced breast cancer. We also discuss other novel agents and potential future combination treatment options.

Morikawa A1, de Stanchina E et Al. – Phase I study of intermittent high dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases. – Clin Cancer Res. 2019 Apr 15. pii: clincanres.3502.2018. doi: 10.1158/1078-0432.CCR-18-3502.

Background: Lapatinib and capecitabine cross the blood tumor-barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high dose tyrosine kinase inhibitor (TKI) has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS).We derived a rational drug scheduling of intermittent high dose lapatinib alternating with capecitabine-basedon our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in breast cancer patients with CNS metastasis.

Methods: We conducted a phase I trial using an accelerated dose escalation design in HER2-positive breast cancer patients with CNS metastasis. Lapatinib was given Day 1-3 and Day 15-17 with capecitabine on Day 8-14 and Day 22-28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1500mg BID. Toxicity and efficacy were evaluated.

Results: Eleven patients were enrolled: brain only (four patients,36%), leptomeningeal, (five patients,45%), and intramedullary spinal cord (two patients,18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The maximum tolerated dose of lapatinib was 1500mg BID. Three patients remained on therapy for greater than six months

Conclusions: High dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in HER2-positive breast cancer patients with CNS metastasis and warrants further investigation.

Xie F, Chen R – Efficacy of two-weekly nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy for breast cancer. – Nanomedicine (Lond). 2019 Apr 12. doi: 10.2217/nnm-2018-0485.

Background: Compare the two-weekly regimens of nanoparticle albumin-bound paclitaxel (nab-P) with solvent-based paclitaxel (sb-P) as neoadjuvant chemotherapy for breast cancer.

Methods: Patients (n = 162) with operable early breast cancer received four cycles of dose-dense epirubicin and cyclophosphamide followed by four two-weekly cycles of nab-P (n = 83) or sb-P (n = 79), with trastuzumab when needed.

Results: Across all the patients, the ypT0 ypN0 and ypT0/is ypN0 pathological complete response rates in the nab-P group were not superior to those in the sb-P group. However, pathological complete response rates for triple-negative breast cancer were significantly better with nab-P than with sb-P. Meanwhile, nab-P also induced more peripheral sensory neuropathy.

Conclusions: The two-weekly nab-P regimen is a good neoadjuvant chemotherapy choice for triple-negative breast cancer.

Baez-Vallecillo L, Raghavendra AS et Al. – Lapatinib activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab, pertuzumab, and/or ado-trastuzumab emtansine (T-DM1). – Breast Cancer Res Treat. 2019 Apr 11. doi: 10.1007/s10549-018-05081-z.

Background: Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies, respectively. The goal of this study was to assess the efficacy of L in a contemporary patient population that received prior P and/or T-DM1.

Methods: We identified patients with HER2-positive MBC who received L (n = 520) between 2003 and 2017 at MD Anderson Cancer Center and selected a target cohort who received L after prior P or T-DM1 (n = 43) with the remaining included in the comparison cohort (n = 477). We evaluated outcome measures including clinical benefit rate (CBR), best tumor response (BTR), duration on L, and time to progression (TTP). Survival analyses used Kaplan-Meier statistics.

Results: CBR was 28% (95% CI 10-32) for the target cohort and 40% (95% CI 36-45) for the comparison cohort. The median duration on L was 5 months (95% CI 3.0-9.0) in the target cohort and 6.7 months (5.9-8.0) in the comparison cohort. In both cohorts, the median time to progression (TTP) and overall survival (OS) were longer in patients with de novo metastatic disease compared to patients with disease recurrence.

Conclusions: L-based therapy is an active therapeutic option and remains a viable option for HER2 + MBC after prior trastuzumab, P and/or T-DM1