"Positioning of tucatinib in the new clinical scenario of HER2-positive metastatic breast cancer: An Italian and Spanish consensus paper".

INTRODUCTION: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. METHODS: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. RESULTS: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. CONCLUSION: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights.

Type does matter. Use VIRGIN olive oil as your preferred fat to reduce your risk of breast cancer: case-control EpiGEICAM study.

The Epi-GEICAM study comprises 1017 invasive BC cases matched with controls of similar age (49 ± 9 years) and residence. Diet and OO consumption were collected through a validated food frequency questionnaire. 75% of women referred OO, common (refined) or virgin, as the main fat source. Using conditional logistic regression models, we compared different scenarios of type and frequency of OO consumption, using as reference those women not always using OO for the three culinary practices (seasoning, cooking, and frying) and adding <2 tablespoons (tbsps.) per day during the meal to bread, salad, or dishes. A substantial inverse association was observed in those women always using VOO for the three culinary practices and consuming ≥2 tbsps. of OO per day during meals (adjusted OR, 0.72; 95% CI: 0.51, 1.03; P = 0.07). Potential benefits from OO consumption, at least as regards the protection provided for BC, could be mostly conferred with VOO, and when its consumption is high.

Early Imaging and Molecular Changes with Neoadjuvant Bevacizumab in Stage II/III Breast Cancer.

This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2-C5). Tumour proliferation and hypoxic status were evaluated using 18F-fluoro-3'-deoxy-3'-L-fluorothymidine (FLT)- and 18F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p ≤ 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.

Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor-Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2-Based Therapy.

PURPOSE: We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer. EXPERIMENTAL DESIGN: Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012). CONCLUSIONS: In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.

CDK4/6 Inhibitors in Hormone Receptor-Positive Metastatic Breast Cancer: Current Practice and Knowledge.

Treatment paradigms in advanced hormone receptor (HR)-positive breast cancer were substantially transformed with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) approval. The addition of these drugs to endocrine treatment profoundly improved progression-free and overall survival. Additionally, other important endpoints, such as the response rate, time to chemotherapy, and a delay in quality of life deterioration, were positively impacted by CDK4/6 inhibitors' addition to the treatment of advanced HR-positive breast cancer. This review article will summarize current knowledge on CDK4/6 inhibitors in clinical practice for advanced HR-positive metastatic breast cancer, as well as describe recent efforts to more precisely characterize mechanisms of sensitivity and resistance to these drugs, both on the molecular and clinical characterization level.

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer.

The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.

Contextualizing pertuzumab approval in the treatment of HER2-positive breast cancer patients.

The use of adjuvant pertuzumab in HER2-positive early-stage breast cancer has recently been approved by the EMA on the basis of data from the APHINITY trial. Accordingly, we have produced this opinion article with the aim of putting the study data in perspective against other add-on therapeutic strategies, to clarify methodological or statistical doubts about the study, and to define the population of high-risk patients with hormone receptor-negative breast cancer that we agree, in general, should be treated. With this approval, physicians must be well prepared to place the APHINITY study data in context. It is now up to each country to ratify the EMA-approved indications and to agree on reimbursement, and doctors must optimize their use based on knowledge and discussion with patients.

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01).

PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.

Successful Second-Line Metronomic Temozolomide in Metastatic Paraganglioma: Case Reports and Review of the Literature.

Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B (SDHB) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB-related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses.

A survey of perceptions, attitudes, knowledge and practices of medical oncologists about cancer pain management in Spain.

PURPOSE: To monitor oncologists' perspective on cancer pain management. METHODS: An anonymized survey was conducted in two waves. First, over a convenience sample of oncologists known to be particularly concerned with the management of pain. Second, using a random sample of oncologists. RESULTS: In total, 73 and 82 oncologists participated in the first and second wave, respectively. Many oncologists reported to have good knowledge of analgesic drugs (95.9%), the mechanism of action of opioids (79.5%), and good skills to manage opioid-related bowel dysfunction (76.7%). Appropriate adjustment of background medication to manage breakthrough pain was reported by 95.5% of oncologists. Additionally, 87.7% (68.3% in the second wave, p = 0.035) of oncologists reported suitable opioid titration practices, and 90.4% reported to use co-adjuvant medications for neuropathic pain confidently. On the other hand, just 9.6% of oncologists participated in multidisciplinary pain management teams, and merely 30.3 and 27.1% reported to routinely collaborate with the Pain Clinics or involve other staff, respectively. Only 26.4% of the oncologists of the second wave gave priority to pain pathophysiology to decide therapies, and up to 75.6% reported difficulties in treating neuropathic pain. Significantly less oncologists of the second wave (82.9 vs. 94.5%, p = 0.001) used opioid rotation routinely. CONCLUSIONS: Unlike in previous surveys, medical oncologists reported in general good knowledge and few perceived limitations and barriers for pain management. However, multi-disciplinary management and collaboration with other specialists are still uncommon. Oncologists' commitment to optimize pain management seems important to improve and maintain good practices.

Frequency of breast cancer with hereditary risk features in Spain: Analysis from GEICAM "El Álamo III" retrospective study.

PURPOSE: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. METHODS: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. RESULTS: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. CONCLUSIONS: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.

Equity, barriers and cancer disparities: study of the Spanish Society of Medical Oncology on the access to oncologic drugs in the Spanish Regions.

PURPOSE: The Spanish Society of Medical Oncology (SEOM) has conducted a study on the access to oncologic drugs across the 17 Spanish Regions with the aim of identifying potential heterogeneities and making proposals for eliminating the barriers identified at the different levels. METHODS: An Expert Panel made up of medical oncologists designed a survey on certain indications approved for 11 drugs in the approach of breast cancer, melanoma, lung cancer, prostate cancer and support treatment. This survey was sent to 144 National Health System (NHS) hospitals. RESULTS: 77 hospitals answered the survey. The information modules analysed were: scope of the Commission that establishes binding decisions related to drug access; conditions, stages and periods of drug application, approval and administration processes; barriers to accessing drugs. CONCLUSIONS: The study shows variability in drug access. The SEOM makes proposals addressed to reducing the differences identified and homogenizing drug access conditions.

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane.

Phase 1 dose escalation and pharmacokinetic evaluation of oral gemcitabine prodrug (LY2334737) in combination with docetaxel in patients with advanced solid tumors.

PURPOSE: This Phase 1 study aimed to determine the recommended Phase 2 dose of LY2334737, an oral gemcitabine prodrug, when combined with standard dose docetaxel treatment in patients with advanced solid tumors. Pharmacokinetics (PK) and antitumor activity were additionally evaluated. METHODS: Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily (QD) for 14 days, followed by a 7-day drug-free period. Docetaxel was given at 75 mg/m(2) every 3 weeks (q3w). Cycles were repeated until progressive disease (PD) or unacceptable toxicity. RESULTS: Of 22 patients recruited, all Caucasian, 7 received an LY2334737 dose of 10 mg/day, 10 received 20 mg/day, 5 received 30 mg/day. Nineteen patients discontinued due to PD, 2 due to adverse events, 1 due to investigator decision. Dose-limiting toxicities: 2× febrile neutropenia (G3), 2× fatigue (1× G2, 1× G3), 1× neutropenia (G4). The maximum tolerated dose (MTD) was identified to be 10 mg/day. Two patients achieved partial response, 10 patients stable disease. Enrollment was stopped after unexpected hepatic toxicities were observed with LY2334737 QD for 14 days per cycle in another study of Japanese patients. PK data were consistent with the first-in-man study of LY2334737 and did not reveal any drug-drug interaction between LY2334737 and docetaxel. CONCLUSIONS: Combination of LY2334737 at doses up to 30 mg/day QD for 14 days per cycle with docetaxel 75 mg/m(2) q3w resulted in an undesirable toxicity profile and a low MTD of 10 mg/day. Alternative treatment schedules of LY2334737 should be explored.

A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.

Denosumab for the treatment of bone metastases in advanced breast cancer.

In women with advanced breast cancer, approximately three-quarters develop metastases to the bone, with a median survival after diagnosis of 2-3 years. Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) belong to a signal pathway highly implicated in the development of bone metastases. Denosumab, a human monoclonal antibody with high affinity and specificity for RANKL, prevents the RANKL/RANK interaction and inhibits osteoclast formation and function, thereby decreasing bone resorption and increasing bone mass. Denosumab compared with zoledronic acid showed superior efficacy in delaying time to first-on study SRE and time to first- and subsequent-on study SREs as well as reduction in bone turnover markers. These results led to the approval of denosumab by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), for the prevention of SREs in adults with bone metastases from solid tumors, including breast cancer.

Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer.

UNLABELLED: Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. PATIENTS AND METHODS: In this single-arm, multicenter, open-label phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m(2) (first cycle dose 60 mg/m(2)) day 1 and day 8, plus capecitabine at 1000 (750 if ≥ 65 years) mg/m(2) twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. RESULTS: Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for ≥ 6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8-16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). CONCLUSION: The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile.

Severe thrombocytopenia related to long-term trastuzumab exposure.

Drug-induced immune thrombocytopenia may occur secondary to several chemotherapeutic agents or new targeted monoclonal antibodies, but thrombocytopenia induced by trastuzumab is a very rare occurrence. We report a case of severe thrombocytopenia related to the administration of trastuzumab six months after the first exposure.