Aleix Prat

The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2

Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR+/HER2+ breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR+/HER2+ breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-HER2 therapy in postmenopausal women with HR+/HER2+ advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR+/HER2+ breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR+/HER2+ advanced breast cancer.

Successful treatment of pulmonary metastatic salivary ductal carcinoma with trastuzumab-based therapy.

Salivary ductal carcinoma (SDC) is an uncommon malignant tumor of the salivary glands. Although there is no known standard of care for the treatment of advanced disease, the vast majority of patients with SDC may be offered palliative systemic therapy. We report a case of epidermal growth factor receptor 2 (HER2)‐positive metastatic submandibular SDC with a complete and durable clinical response to treatment with trastuzumab in combination with chemotherapy.

Update on novel therapeutic agents for cervical cancer

Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer. In recent years, significant improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of new targets and agents for clinical testing. Two of these promising targets are epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathway, which play critical roles in tumor growth and angiogenesis. Two monoclonal antibodies, cetuximab, which targets EGFR, and bevacizumab, which target the VEGF signaling pathway, are being evaluated as monotherapy and in combination with other agents and/or radiotherapy for the treatment of cervical cancer. In addition, VEGF receptor tyrosine kinase inhibitors, such as sorafenib and pazopanib, are being studied in phase I/II clinical trials. In this review, we discuss potential molecular targets and novel therapeutic strategies that are being investigated for the treatment of cervical cancer.

Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels

BACKGROUND Our group evaluated the risk of recurrence for optimally treated advanced epithelial ovarian cancer (adEOC) in patients with a low-level rising serum CA-125 concentration within the normal range (0-35 kU/l). In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population. PATIENTS AND METHODS Patients treated from 1998 to 2006 for adEOC were identified at our institution. Inclusion criteria were as follows: CA-125 at time of diagnosis (>35 kU/l); International Federation of Gynecology and Obstetrics stages III-IV treated with optimal primary treatment; and complete response (CR) to primary treatment with normalization of CA-125. RESULTS Median progression-free survival and overall survival for the recurrence group (n = 60) were 17.7 and 38.2 months, respectively. The median follow-up time from CR to last contact was 40.2 months for patients in the nonrecurrence group (n = 36). An absolute increase in serum CA-125 levels of >or=5 kU/l compared with baseline CA-125 nadir values was significantly predictive of recurrence (odds ratio for recurrence = 402.98, P < 0.0001). The progression date was predated by the EPD criterion in 77% of patients with known progressive disease (median, 58 days early) with a sensitivity of 90%, a positive predictive value of 96.4%, and a false-positive rate of 5.6%. CONCLUSIONS Among patients with optimally treated adEOC in complete remission, a low-level increase in serum CA-125 concentration within the normal range is a strong independent predictive factor for disease recurrence. In this patient population, future prospective randomized trials should consider the evaluation of the EPD criterion.

Clinical surrogate markers of survival in advanced non-small cell lung cancer (NSCLC) patients treated with second–third line erlotinib

BACKGROUND Inhibition of the EGFR pathway is a useful strategy in the treatment of patients with advanced NSCLC. The aim of this study is to assess predictive clinical parameters of efficacy. METHODS AND PATIENTS Sixty-two patients with advanced NSCLC were treated with erlotinib as second-third line (150 mg/day). Baseline patient characteristics were: performance status (PS) 1: 92%; median age, 58 years; males, 73%; adenocarcinoma, 45%; current/former smokers, 83%. During erlotinib treatment, 35% of patients had no rash, 32.3% had grade 1 rash, 26% had grade 2 rash and 6.5% patients developed grade 3 rash. RESULTS For patients with grades 2-3 rash vs. those with grades 0-1 rash, time to tumor progression (TTP) and overall survival (OS) were 92 vs. 41 days (p=0.0381) and 244 vs. 131 days (p=0.011), respectively. For patients with non-smoking history and current/former smokers, TTP and OS were 136 vs. 42 days (p=0.0015) and 324 vs. 133 days (p=0.0242), respectively. In addition, rash grade and smoking history were found to have a highly significant impact on TTP and OS, according to the Cox model. CONCLUSIONS Grade > or =2 rash and non-smoking history are associated with improved TTP and OS in advanced NSCLC patients treated with erlotinib.

Abstract P6-01-06: Feasibility of the PROSIGNA® multigene test in core biopsies and comparison to corresponding surgical breast cancer sections

Background: The PROSIGNA® (PAM50) gene assay has been validated on formalin-fixed paraffin embedded (FFPE) surgical resection specimens (SRS) to identify the intrinsic subtypes of breast cancer and to estimate the 10-year risk of recurrence (ROR) in post-menopausal patients treated with adjuvant endocrine therapy. However, demonstration of the ability to perform PAM50 assay in diagnostic core biopsy specimens (CBS) before primary surgery and/or systemic therapy could be clinically useful. The objectives of this study were to 1) evaluate the feasibility of performing the PAM50 assay in CBS and 2) compare the PAM50 results from paired CBS and SRS. Methods and materials: Baseline tissue surface area, cellularity and RNA yield (obtained after ∼10 FFPE 10μm sections) were determined in CBS from 30 newly diagnosed breast cancer patients. The tissue volume requirements determined from these samples reflected the lower 95% confidence limits of a minimum RNA concentration of >20ng/µL. The RNA yield and assay pass rate of the established tissue volume requirements were then tested in 30 independent CBSs. Intrinsic subtype concordance, and ROR score variability, were determined from 1) multiple extractions of the same CBS (10 independent cases for a total of 84 extractions) and 2) multiple CBS of the same tumor (30 independent cases for a total of 79 CBS). To test the PAM50 assay concordance between paired CBS and SRS, the following PAM50 data were evaluated in an independent and retrospective set of 33 paired samples: 4-class subtype classification (Luminal A, Luminal B, HER2-enriched and Basal-like), 3-class subtype classification (Luminal A/B, HER2-enriched and Basal-like), ROR score (0-100), proliferation score and the correlation to each subtype centroid. Correlation and concordance between CBS and SRS were estimated using Pearson coefficients and multi-rater kappa values, respectively. Results: Baseline median surface area, cellularity and RNA yield concentration were 10.2 mm2, 45% and 155.3 ng/µl, respectively. Correlation of surface area and cellularity with RNA yield concentration was low (Person coefficient 12 mm2 = 2 10-micron slides, 6-12 mm2 = 4 slides; 95%. Conclusions: The PAM50 assay in CBS is feasible and measurements are comparable with surgical resections, which suggest that PAM50 can be performed on diagnostic core biopsy tissues. Citation Format: Aleix Prat, Patricia Galvan, Wesley Buckingham, Maria Vidal, Sherley Diaz, Paolo Nuciforo, Sean Ferree, Barbara Adamo, Santiago Ramon y Cajal, Vicente Peg. Feasibility of the PROSIGNA® multigene test in core biopsies and comparison to corresponding surgical breast cancer sections [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-06.

Abstract P4-12-01: Molecular features and survival outcomes of the intrinsic subtypes of breast cancer based on HER2 gene amplification

Background: HER2-amplified (HER2+) breast cancer is biologically heterogeneous and all the intrinsic molecular subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) can be identified. However, the molecular and outcome differences of the intrinsic subtypes based on HER2 status have not been thoroughly studied. This is important since HER2 is considered an oncogene involved in the activation of various signal transduction pathways, as well as a biomarker of poor prognosis (in the absence of anti-HER2 targeting). Methods: To compare molecular features between clinically HER2+ and HER2-negative tumors, we interrogated The Cancer Genome Atlas (TCGA) publicly available dataset of 825 primary breast cancers with at least one of following data types: mRNA expression (17,784 genes), protein expression (171 proteins and phospho-proteins), DNA methylation status (574 probes), miRNA expression (306 transcripts) and whole exome somatic mutations. Two-class unpaired Significant Analyses of Microarrays were used to identify significant biomarker associations with a False Discovery Rate of 0%. For survival associations, we interrogated the METABRIC DNA copy number/gene expression-based dataset (Curtis et al. Nature) composed of 1,971 primary breast tumors with long-term clinical follow-up (and no adjuvant anti-HER2 therapy). Multivariable Cox models were used to test the prognostic significance of each variable. The research based 50-gene PAM50 model was used to classify tumors into the different intrinsic subtypes. Results: In both datasets combined (n = 2,225), HER2+ disease showed an enrichment for HER2-enriched tumors (47.0% vs. 7.1%) and a decrease in Luminal A tumors (7.3% vs. 39.0%) compared to HER2-negative disease (p Conclusions: When the intrinsic subtypes are taken into account, HER2 amplification does not translate into large changes in the activation of downstream signaling pathways or worse patient survival outcomes. These results also suggest that the potential responses to anti-HER2 therapy on HER2-amplified tumor cells depend in part upon their intrinsic tumor profile. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-01.

Cutaneous rash as a surrogate marker of time to tumor progression (TTP) with erlotinib in previously treated advanced non- small cell lung cancer (NSCLC)

19125 Background: Inhibition of the EGFR pathway has become an established strategy in NSCLC patients (pts) treatment. The aim of this study is to assess the value of predictive clinical variables associated with outcome in advanced NSCLC pts treated with erlotinib. Methods: Pts (n = 62) from a phase II trial with advanced NSCLC were treated with erlotinib (150 mg/day) upon chemotherapy (CT) progression. Pts characteristics were: performance status (PS), 0–1, 100%; median age, 58 years; males, 73%; adenocarcinoma, 45%; smoking history, 83%. Cutaneos rash during erlotinib: grade 0, 22 pts (35%); grade 1, 20 pts (32%); grade 2, 16 pts (26%); grade 3, 4 pts (7%). Standard Kaplan-Meier methods were used to plot the TTP of members of each group. The relative contribution of the different potential correlates of prognosis was assessed by the Cox proportional hazards method. Results: Partial response was noted in 6 pts (9.6%) and stable disease in 16 (26%). The median TTP was 43 days (95% confidence interval 19–...