Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Metronomic oral chemotherapy with cyclophosphamide plus capecitabine combined with trastuzumab (HEX) as first line therapy of HER-2 positive advanced breast cancer: A phase II trial of the Gruppo Oncologico Italia Meridionale (GOIM).

BACKGROUND: The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC.Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. RESULTS: Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1-98). ORR was 56.7% (95% CI, 44.1-68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3-4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. CONCLUSIONS: Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer patients: safety and efficacy. An Italian experience.

BACKGROUND: Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer (BC). Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting. METHODS: Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported. RESULTS: Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2-9). The median number of cycles with E/T was 11.5 (range 2-26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%). CONCLUSIONS: Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.

Final results of a prospective study of scalp cooling in preventing chemotherapy-induced alopecia.

Aim: Alopecia is a distressing effect of cancer treatments. Our study examined efficacy and safety of scalp cooling to prevent chemotherapy-induced alopecia. Materials & methods: Early breast cancer patients candidate to anthracycline and/or taxane were eligible. Dean's alopecia scale was used to classify alopecia. Results: From February 2016 to November 2018, 127 women were enrolled; 55 (43.3%) received epirubicin/cyclophosphamide (4 EC 3 weeks) followed by paclitaxel (12 P weeks); 50 (39.4%) received 4 EC 3 weeks; 20 (15.7%) received 12 P weeks/trastuzumab and 2 docetaxel/cyclophosphamide (4 TC 3 weeks). The success rate was 71.7% (G0 21.3%, G1 31.5%, G2 18.9%). Frequent side effects were: coldness, headache, scalp pain and head heaviness. Conclusion: In our study, scalp cooling can prevent alopecia thus supporting the wider use in early breast cancer.

Discordance in pathology report after central pathology review: Implications for breast cancer adjuvant treatment.

AIM: Pathological predictive factors are the most important markers when selecting early breast cancer adjuvant therapy. In randomized clinical trials the variability in pathology report after central pathology review is noteworthy. We evaluated the discordance rate (DR) and inter-rater agreement between local and central histopathological report and the clinical implication on treatment decision. METHODS: A retrospective analysis was conducted in a series of consecutive early breast cancer tumors diagnosed by local pathologists and subsequently reviewed at the Pathology Division of European Institute of Oncology. The inter-rater agreement (k) between local and central pathology was calculated for Ki-67, grading, hormone receptors (ER/PgR) and HER2/neu. The Bland-Altman plots were derived to determine discrepancies in Ki-67, ER and PgR. DR was calculated for ER/PgR and HER2. RESULTS: From 2007 to 2013, 187 pathology specimens from 10 Cancer Centers were reviewed. Substantial agreement was observed for ER (k0.612; 95% CI, 0538-0.686), PgR (k0.659; 95% CI, 0580-0.737), Ki-67 (k0.609; 95% CI, 0.534-0.684) and grading (k0.669; 95% CI, 0.569-0.769). Moderate agreement was found for HER2 (k0.546; 95% CI, 0444-0.649). DR was 9.5% (negativity to positivity) and 31.7% (positivity to negativity) for HER2 and 26.2% (negativity to positivity) and 12.5% (positivity to negativity) for ER/PgR. According to changes in Her2 and ER/PgR status, 23 (12.2%) and 33 (17.6%) systemic prescription were respectively modified. CONCLUSIONS: In our retrospective analysis, central pathological review has a significant impact in the decision-making process in early breast cancer, as shown in clinical trials. Further studies are warranted to confirm these provocative results.

Response of extensive breast cancer skin metastases to rechallenge with trastuzumab together with low-dose chemotherapy and insulin.

INTRODUCTION: Cutaneous metastasis occurs in about 29% of breast cancer patients and has a deep impact on patient quality of life. METHODS: A 60-year-old woman with cutaneous metastases from heavily pretreated HER2-positive breast cancer received CMFVP (oral cyclophosphamide 100 mg daily; oral prednisone 12.5 mg daily for 2 weeks, then 7.5 mg daily; intravenous weekly methotrexate 25 mg/m2, 5-5-fluorouracil 400 mg/m2 and vincristine 0.5 mg) with weekly trastuzumab and subcutaneous insulin until disease progression. RESULTS: From March 2009 to November 2009 the patient was treated with the described regimen. At the best response, we observed the disappearance of some lesions and cessation of bleeding and thoracic pain. Time to progression was 8 months. CONCLUSIONS: Our patient had clinical benefit from reintroduction of trastuzumab, low-dose chemotherapy and insulin. The explanation of this prolonged response is only speculative and requires further clinical confirmation in the treatment strategy of HER2-positive breast cancer.

Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience.

AIMS AND BACKGROUND: Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). METHODS: The aim of this study is to assess if panitumumab has some activity in this setting. RESULTS: We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease ≥5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). CONCLUSIONS: Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary.

Recent advances in the treatment of hormone receptor positive HER2 negative metastatic breast cancer.

Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC). However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options for this patients. In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors. Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or stratified by pathways amplification.

BMI variation increases recurrence risk in women with early-stage breast cancer.

AIMS: The prognostic role of BMI variation during and/or after treatments for early-stage breast cancer is still unknown. PATIENTS & METHODS: The χ(2) test was conducted to explore the correlation between breast cancer recurrence and BMI changes in 520 early-stage breast cancer patients. Cox proportional hazard models were used to analyze the association of BMI changes, baseline BMI, known prognostic factors and recurrences. RESULTS: BMI gain was significant determinant of recurrences (p = 0.0008). In multivariate analyses, BMI variation more than 5.71% was associated with higher rates of recurrences, as well as age less than 55 years, stage disease and molecular subtype. CONCLUSION: Women who experience BMI gain after breast cancer may be at increased risk of poor outcomes.

Clinical outcomes and cardiac safety of continuous antiHer2 therapy in c-erbB2-positive metastatic breast cancer patients.

BACKGROUND: To explore clinical outcomes and cardiac safety of continuous antiHer2 therapy. PATIENTS AND METHODS: This retrospective study evaluates overall survival (OS), time to treatment failure (TTF), and cardiac safety of 80 consecutive Her2-positive metastatic breast cancer (MBC) patients that received ≥ 12 months of therapy with trastuzumab, followed by lapatinib-based or trastuzumab-based therapy. RESULTS: All patients received trastuzumab as first antiHer2 therapy; 54% received lapatinib in the second or subsequent line. Median OS was 34 months (12-120 months). Median OS was 48 months in the subgroup of 43 patients who received lapatinib and 26 months in the 37 patients who did not. Median TTF was shorter for lapatinib. There were three cardiac events and trastuzumab-based chemotherapy (CT) was interrupted in one patient because left ventricular ejection fraction (LVEF) decreased to ≤ 40%. CONCLUSION: Continuous antiHer2 therapy provides good clinical outcomes, especially in those patients who received lapatinib. Cardiac dysfunction was a rare event, reversible, associated to trastuzumab and not related to treatment duration.

Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going?

Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design. More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone. The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance.

Poly (ADP-ribose) polymerase (PARP): rationale, preclinical and clinical evidences of its inhibition as breast cancer treatment.

INTRODUCTION: The chance to take advantage of genetic defects of cancer cells is a promising clinical tool in breast cancer therapy. Among the genetic aberrations, dysfunctions in DNA repair mechanisms are quite common and suitable for an attractive antitumor effect. Poly (ADP-ribose) polymerase I (PARP-1) is an enzyme with many functions in transcriptions and cell cycle regulation and in coordination of cellular response to DNA damage. Its involvement in tumorigenesis is witnessed by the overexpression found in different primary human tumors, where the increased enzymatic activity leads to cancer cell protection against DNA damage and instability. Therefore, activity of PARP and the opportunity to block it, mainly in cancer cells also deficient in other mechanisms of repair, are promising. AREAS COVERED: In this review, areas covered include the main DNA repair mechanisms, the role of PARP enzymatic activity in diverse cell pathways as well as the preclinical and clinical data with PARP inhibitors. EXPERT OPINION: Despite the theoretical role of PARP inhibitors as therapeutic strategy in specific subtypes of breast cancer (hereditary BRCA1/BRCA2 mutation-related cancers and sporadic triple-negative breast cancer), questions are still open. More exhaustive knowledge is needed about other important functions of PARPs in cellular homeostasis and about escape mechanisms of cancer cells to inhibitory effect of PARP inhibitors.