Attualità in Senologia

Rassegna della letteratura: gennaio/marzo 2020
Oncologia medica e terapie per il controllo sistemico

The Utility of Oncotype DX for Adjuvant Chemotherapy Treatment Decisions in Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative, Node-negative Breast Cancer.
Rizki H, Hillyar C, Abbassi O3 – Cureus 2020 Mar 14;12(3):e7269
Introduction Breast cancer is the most common cancer diagnosis in the UK. Recently, there has been a reduction in breast cancer-specific mortality and recurrence attributed, in part, to the delivery of adjuvant chemotherapy. The National Institute for Health and Care Excellence (NICE) recommends the use of genetic profiling with Oncotype DX (ODX) to guide decisions to offer adjuvant chemotherapy after surgery in intermediate-risk early breast cancer patients. This study aimed to evaluate the utility of ODX testing in routine clinical practice in a National Health Service (NHS) hospital.  Methods Consecutive early breast cancer patients, identified through the multidisciplinary team (MDT) records, treated in our institution over 12 months (October 2017-September 2018) were included. PREDICT and Nottingham prognostic index (NPI) scores (from online clinicopathological recurrence risk tools) were calculated for each patient, and ODX data obtained through Genomic Health, Inc. (Redwood City, California). Patients were divided into two groups, those that underwent ODX testing (ODX group) and those that did not (non-ODX group). Descriptive statistics were used to analyse patient and tumour characteristics. The Gaussian distribution of each data set was assessed using the Anderson-Darling test. For comparisons between patient groups, the non-parametric equivalent of the two-tailed t-test (Mann-Whitney) was used. Dichotomous variables (e.g. chemotherapy decisions) were compared using chi-squared tests. Results One-hundred thirty-three patients (mean age 62 years) treated for 152 early breast cancers, were included in the final analysis. Breast cancers in the ODX group were of greater median tumour size (24 vs 16 mm; P<0.0001) and higher median tumour grade (3 vs 2; P<0.0001). PREDICT scores (3 vs 1, P<0.0001) and NPI scores (3.40 vs 2.30, P<0.0001) for the ODX group were also significantly higher than the non-ODX group. A greater proportion of patients were offered chemotherapy in the ODX group (39.9% vs 6.9%, P<0.001). However, for the PREDICT-calculated intermediate-risk patients, ODX testing resulted in a lower proportion of patients being offered chemotherapy compared to the intermediate-risk patients who were not genetically profiled (54.5% vs 83.3%, P=0.3547), although this result was not statistically significant. Conclusions Patients selected for ODX testing were younger, with significantly higher-grade and larger-sized tumours compared to patients not selected for genetic profiling. ODX testing significantly impacted the delivery of chemotherapy, as the recurrence score generated through ODX testing guided the final decision.

Biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer.
Iwamoto T, Kajiwara Y et Al – Chin Clin Oncol. 2020 Mar 13.
The improvement of tumor biomarkers prepared for clinical use is a long process. A good biomarker should predict not only prognosis but also the response to therapies. In this review, we describe the biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer, considering different breast cancer subtypes. In hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative breast cancers, various genomic markers highly associated with proliferation have been tested. Among them, only two genomic signatures, the 21-gene recurrence score and 70-gene signature, have been reported in prospective randomized clinical trials and met the primary endpoint. However, these genomic markers did not suffice in HER2-positive and triple-negative (TN) breast cancers, which present only classical clinical and pathological information (tumor size, nodal or distant metastatic status) for decision making in the adjuvant setting in daily clinic. Recently, patients with residual invasive cancer after neoadjuvant chemotherapy are at a high-risk of recurrence for metastasis, which, in turn, make these patients best applicants for clinical trials. Two clinical trials have shown improved outcomes with post-operative capecitabine and ado-trastuzumab emtansine treatment in patients with either TN or HER2-positive breast cancer, respectively, who had residual disease after neoadjuvant chemotherapy. Furthermore, tumor-infiltrating lymphocytes (TILs) have been reported to have a predictive value for prognosis and response to chemotherapy from the retrospective analyses. So far, TILs have to not be used to either withhold or prescribe chemotherapy based on the absence of standardized evaluation guidelines and confirmed information. To overcome the low reproducibility of evaluations of TILs, gene signatures or digital image analysis and machine learning algorithms with artificial intelligence may be useful for standardization of assessment for TILs in the future.

Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond.
Costa RLB , Czerniecki BJ – NPJ Breast Cancer. 2020 Mar 12;6:10.
Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ~25% of breast cancer cases. Monoclonal antibodies (mAbs) against HER2 have led to unparalleled clinical benefit for a subset of patients with HER2+ breast cancer. In this narrative review, we summarize advances in the understanding of immune system interactions, examine clinical developments, and suggest rationales for future investigation of immunotherapies for HER2+ breast cancer. Complex interactions have been found between different branches of the immune system, HER2+ breast cancer, and targeted treatments (approved and under investigation). A new wave of immunotherapies, such as novel HER2-directed mAbs, antibody drug conjugates, vaccines, and adoptive T-cell therapies, are being studied in a broad population of patients with HER2-expressing tumors. The development of immunotherapies for HER2+ breast cancer represents an evolving field that should take into account interactions between different components of the immune system.

Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial.
Gennari A, Foca F, Zamarchi R et Al. – Breast Cancer Res Treat. 2020 Mar 21.
Background:  To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients
Methods: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses.
Results:  Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found
Conclusions:  Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategiesChoose Destination

Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study.
Blondeaux , Lambertini M, Michelotti A et Al. – Br J Cancer. 2020 Mar 31.
Background:  Adjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown.
Methods: In the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS).
Results:  From 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51-1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51-0.96).
Conclusions:  Updated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Is There Still a Role for Endocrine Therapy Alone in HR+/HER2- Advanced Breast Cancer Patients? Results from the Analysis of Two Data Sets of Patients Treated with High-Dose Fulvestrant as First-Line Therapy in the Real-World Setting: The EVA and GIM-13 AMBRA Studies.
Cazzaniga ME, Verusio C, Ciccarese M  et Al – Breast Care (Basel). 2020 Feb;15(1):30-37.
Background:  Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting.
Methods: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies)
Results:  Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35-82) for the EVA and 57.8 years (range 35.0-82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1-48) and 12.4 months (range 2.9-70.0) in the two data sets, respectively
Conclusions:  These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

Muscle mass loss after neoadjuvant chemotherapy in breast cancer: estimation on breast magnetic resonance imaging using pectoralis muscle area.
Rossi F, Torri L, Lambertini M et Al. – Eur Radiol. 2020 Mar 31.
Background:  The loss of skeletal muscle mass is widely considered a predictor of poor survival and toxicity in breast cancer patients. The aim of this study is to evaluate if there is pectoralis muscle area (PMA) variation, reflecting loss of skeletal muscle mass, on consecutive MRI examinations after neoadjuvant chemotherapy.
Methods: The retrospective study protocol was approved by our institutional review board. A total of n = 110 consecutive patients (mean age 56 ± 11 years) who were treated with neoadjuvant chemotherapy (NAC) for histologically proven primary breast cancer between January 2017 and January 2019 and in whom tumor response was checked with standard breast MRI were included. Two radiologists calculated the pectoralis muscle cross-sectional area before and after NAC.
Results:  Time between the MRI examinations, before starting NAC and after completing NAC, was 166.8 ± 50 days. PMA calculated pre-NAC (8.14 cm2) was larger than PMA calculated post-NAC (7.03 cm2) (p < 0.001). According to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, there were no significant differences between responders (complete or partial response) and non-responders (p = 0.362). The multivariate regression analysis did not show any significant relationships between ΔPMA and age, time between MRI exams, estrogen and progesterone receptor status, human epidermal growth factor receptor status (HER-2), Ki-67 expression, lymph node status, RECIST criteria, histological type, average lesion size, molecular categories, and grade. Inter-reader (k = 0.72) and intra-reader agreement (0.69 and 0.71) in PMA assessment were good.

Conclusions: Pectoralis muscle mass varies in breast cancer patients undergoing NAC and this difference can be estimated directly on standard breast MRI.

Ulteriori segnalazioni:

The impact of granulocyte colony-stimulating factor use in patients with metastatic breast cancer treated with palliative chemotherapy: a single-institution retrospective review.
Mousa L, Stephens JA, Berger M et Al – Support Care Cancer. 2020 Mar 17.

Cost-Effectiveness Analysis of Bevacizumab plus Paclitaxel versus Bevacizumab plus Capecitabine for
HER2-Negative Locally Recurrent or Metastatic Breast Cancer.
Wu Q, Wang X, Zhang M, Liao W, Oncol Res Treat. 2020 Mar 18:1-7.

Chemo-Photothermal Therapy in Breast Cancer Using Methotrexate-Loaded Folic Acid Conjugated Au@SiO(2) Nanoparticles.
Agabeigi R, Rasta SH, Rahmati-Yamchi M – Nanoscale Res Lett. 2020 Mar 19;15(1):62.

Nab-paclitaxel and atezolizumab for the treatment of PD-L1-positive, metastatic triple-negative breast cancer: review and future directions.
Kagihara JA, Andress M, Diamond JR. – Expert Rev Precis Med Drug Dev. 2020;5(2):59-65.

Effects of neoadjuvant chemotherapy on respiratory function in patients with breast cancer.
Ding L, Wang L, Yin J, Fan Z, He Z. Chin J Cancer Res. 2020 Feb;32(1):36-42.

Behavior of metastatic breast cancer according to subtype.
Van Mechelen M, Van Herck A, Punie K, Breast Cancer Res Treat. 2020 Mar 19.

Factors Influencing Adjuvant Chemotherapy and Trastuzumab Choice in Older Human Epidermal Growth Factor Receptor 2-positive Breast Cancer Patients.
Fang Y, Wang Z, Wu J, Huang O, J Cancer. 2020 Feb 14;11(9):2602-2609.

Overcome trastuzumab resistance of breast cancer using anti-HER2 chimeric antigen receptor T cells and PD1 blockade.
Li H, Yuan W, Bin S, Wu G, et Al – Am J Cancer Res. 2020 Feb 1;10(2):688-703

Data of Triplet Combination of Trastuzumab, Lapatinib, and Chemotherapy in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study.
Li Y, Gong C, Lu Q, Zhou Z, Luo T et Al –  Oncol. 2020 Mar 3;10:271.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.
Eiger D, Pondé NF, Agbor-Tarh D et Al –  Br J Cancer. 2020 Mar 16

Regulation of docetaxel chemosensitivity by NR2F6 in breast cancer.
Zhang J, Meng H, Zhang M, Zhang C – Endocr Relat Cancer. 2020 Mar 1.

Challenges in the treatment of breast cancer brain metastases: evidence, unresolved questions, and a practical algorithm.
Meattini I, Andratschke N, Kirby AM –  Clin Transl Oncol. 2020 Mar 21

The Evolution of Clinical Trials in Metastatic Breast Cancer: Design Features and Endpoints That Matter.
Seidman AD, Maues J, Tomlin T et Al – Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-11.