Monica Arnedos

Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER)

BACKGROUNDnBreast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals genomic alterations.nnnMETHODSnFrom June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France. Comparative genomic hybridisation (CGH) array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five centres. Therapeutic targets were decided on the basis of identified genomic alterations. The primary objective was to include 30% of patients in clinical trials testing a targeted therapy and, therefore, the primary outcome was the proportion of patients to whom a targeted therapy could be offered. For the primary endpoint, the analyses were done on the overall population registered for the trial. This trial is registered with ClinicalTrials.gov, number NCT01414933.nnnFINDINGSn423 patients were included, and biopsy samples were obtained from 407 (metastatic breast cancer was not found in four). CGH array and Sanger sequencing were feasible in 283 (67%) and 297 (70%) patients, respectively. A targetable genomic alteration was identified in 195 (46%) patients, most frequently in PIK3CA (74 [25%] of 297 identified genomic alterations), CCND1 (53 [19%]), and FGFR1 (36 [13%]). 117 (39%) of 297 patients with genomic tests available presented with rare genomic alterations (defined as occurring in less than 5% of the general population), including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Therapy could be personalised in 55 (13%) of 423 patients. Of the 43 patients who were assessable and received targeted therapy, four (9%) had an objective response, and nine others (21%) had stable disease for more than 16 weeks. Serious (grade 3 or higher) adverse events related to biopsy were reported in four (1%) of enrolled patients, including pneumothorax (grade 3, one patient), pain (grade 3, one patient), haematoma (grade 3, one patient), and haemorrhagic shock (grade 3, one patient).nnnINTERPRETATIONnPersonalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations.nnnFUNDINGnFrench National Cancer Institute, Breast Cancer Research Foundation, Odyssea, Operation Parrains Chercheurs.

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.

Precision medicine for metastatic breast cancer—limitations and solutions

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.

Triple-negative breast cancer: are we making headway at least?

The so-called triple-negative breast cancer, as defined by tumors that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression, has generated growing interest in recent years despite representing less than 20% of all breast cancers. These tumors constitute an important clinical challenge, as they do not respond to endocrine treatment and other targeted therapies. As a group they harbor an aggressive clinical phenotype with early development of visceral metastases and a poor long-term prognosis. While chemotherapy remains effective in triple-negative disease, research continues to further identify potential new targets based on phenotypical and molecular characteristics of these tumors. In this respect, the presence of a higher expression of different biomarkers including epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and Akt activation has led to a proliferation of clinical trials assessing the role of inhibitors to these pathways in triple-negative tumors. Moreover, the described overlap between triple-negative and basal-like tumors, and the similarities with tumors arising in the BRCA1 mutation carriers has offered potential therapeutic avenues for patients with these cancers including poly (ADP-ribose) polymerase inhibitors and a focus on a higher sensitivity to alkylating chemotherapy agents. Results from these trials have shown some benefit in small subgroups of patients, even in single-agent therapy, which reflects the heterogeneity of triple-negative breast cancer and highlights the need for a further subclassification of these types of tumors for better prognosis identification and treatment individualization.

Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in estrogen receptor-positive breast cancer

BACKGROUNDnThe purpose of this study was to identify any differences in key biomarkers associated with estrogen action between biopsies taken at diagnosis and at recurrence or progression during treatment with an aromatase inhibitor (AI).nnnPATIENTS AND METHODSnPatients were retrospectively identified from a clinical database as having relapsed or progressed during AI treatment. Immunohistochemistry was carried out against estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), insulin-like growth factor type-1 receptor (IGF1R), insulin receptor substrate-1 (IRS-1), stathmin, phosphatase and tensin homolog and Ki67.nnnRESULTSnFifty-five pairs of samples were identified with ER- and/or PgR-positive diseases. Four (7%) patients were ER-negative at progression. Overall, PgR levels were lower in the recurrence sample, but 35% of cases remained positive. IGF1R levels decreased significantly. There were no substantial changes in HER2, IRS-1 or stathmin levels to indicate a role in resistance. Higher Ki67 levels at resistance indicate more proliferative disease.nnnCONCLUSIONSnThe phenotype of AI-recurrent lesions shows high between-tumour heterogeneity. There is evidence of an increase in Ki67, a reduction in IGF1R and a loss of ER expression in some individuals and some activation of growth factor signalling pathways that may explain resistance in individuals and merit treatment targeted to those pathways. Biopsy at recurrence will be necessary to identify the relevant target for individuals.BACKGROUNDnThe purpose of this study was to identify any differences in key biomarkers associated with estrogen action between biopsies taken at diagnosis and at recurrence or progression during treatment with an aromatase inhibitor (AI).nnnPATIENTS AND METHODSnPatients were retrospectively identified from a clinical database as having relapsed or progressed during AI treatment. Immunohistochemistry was carried out against estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), insulin-like growth factor type-1 receptor (IGF1R), insulin receptor substrate-1 (IRS-1), stathmin, phosphatase and tensin homolog and Ki67.nnnRESULTSnFifty-five pairs of samples were identified with ER- and/or PgR-positive diseases. Four (7%) patients were ER-negative at progression. Overall, PgR levels were lower in the recurrence sample, but 35% of cases remained positive. IGF1R levels decreased significantly. There were no substantial changes in HER2, IRS-1 or stathmin levels to indicate a role in resistance. Higher Ki67 levels at resistance indicate more proliferative disease.nnnCONCLUSIONSnThe phenotype of AI-recurrent lesions shows high between-tumour heterogeneity. There is evidence of an increase in Ki67, a reduction in IGF1R and a loss of ER expression in some individuals and some activation of growth factor signalling pathways that may explain resistance in individuals and merit treatment targeted to those pathways. Biopsy at recurrence will be necessary to identify the relevant target for individuals.

Biomarker Discovery, Development, and Implementation in France: A Report from the French National Cancer Institute and Cooperative Groups

Biomarkers are increasingly changing the medical practice in oncology. One of the major challenges in the field of personalized medicine or biologically adapted therapies is to ensure a rapid and extensive implementation of emerging biomarkers as soon as proof of their medical usefulness is obtained. A special program has been developed in France to facilitate the assessment and use of biomarkers. The French National Cancer Institute has set up a total of 28 laboratories in public hospitals to perform biomarker testing for clinical use. This program is enabling all patients who present with cancer to receive free testing for biomarkers, such as K-Ras, epidermal growth factor receptor, c-Kit, and Braf mutations. Funding for these laboratories comes from the French Ministry of Health. The future of these laboratories includes the development of DNA arrays and multiplex technologies for clinical use. Toward that end, the French National Cancer Institute is financing several large clinical trials that several large clinical trials are currently evaluating the feasibility and medical utility of DNA arrays and next-generation sequencing in the context of academic centers. The programs are being run by cooperative groups. Clin Cancer Res; 18(6); 1555–60. ©2012 AACR.

Abstract CT041: Anti-proliferative response and predictive biomarkers to palbociclib in early breast cancer: The Preoperative Palbociclib (POP) randomized trial

Background: In this monocentric randomized trial we aimed at identifying if short-term preoperative palbociclib treatment is associated with decreased proliferation and early biomarker changes in patients with early breast cancer (EBC) Methods: Untreated EBC patients were randomized 3:1 to oral palbociclib 125mg daily for 14 days until the day before the surgery vs no treatment. FFPE and frozen samples were extracted at baseline and at surgery. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Immunostaining (Ki67, RB, pRB, p16, pAKT, pER), FISH (CCND1) and gene expression (GE) arrays were performed pre- and post-treatment. PIK3CA and AKT1 mutations were assessed pretreatment. Results: 74 patients were randomized in the palbociclib arm and 26 in the control arm. 93% tumors were HR-positive; 8% HER2-positive. Palbociclib treatment led to significantly more patients with antiproliferative response as compared to control (58% vs 10%, p = 0.0003). In addition, mean decrease from baseline in ln(Ki67) was significantly higher at day 15 in the palbociclib arm (p Citation Format: Monica Arnedos, Bianca Cheaib, Mohamed Amine Bayar, Stefan Michiels, Veronique Scott, Julien Adam, Valerie Leroux-Kozal, Virginie Marty, Chafika Mazouni, Benjamin Sarfati, Ivan Bieche, David Gentien, Suzette Delaloge, Magali Lacroix-Triki, Fabrice Andre. Anti-proliferative response and predictive biomarkers to palbociclib in early breast cancer: The Preoperative Palbociclib (POP) randomized trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT041.

351OGENOMIC AND IMMUNE CHARACTERIZATION OF METASTATIC BREAST CANCER (MBC): AND ANCILLARY STUDY OF THE SAFIR01 & MOSCATO TRIALS

ABSTRACT Aim: So far, little is known about immune and genomic landscape in metastatic breast cancer (mBC). Methods: Patients were retrospectively identified from SAFIR01 and MOSCATO studies that performed molecular screening from a biopsy of a metastatic lesion. Whole exome sequencing (WES) was performed using Hi-Seq technology. Coverage was 50x and 100x for normal and tumoral tissue respectively. Bioinformatic analyses reported mutations and copy number alterations. Immune characterisation was determined by the presence of intratumoral and stromal TILs with PD1 and PDL1 expression assessed by IHC (internal protocol, Medimmune). We correlated tumor characteristics and immune and genomics data. Results: 280 samples were stained for immune analyses. Using a 50% cut-off, few tumors presented intratumoral (n = 3/244, 1%) and stromal (n = 11/244, 5%) TILs. This rate was significantly higher in HER2+ tumors (stromal TIL, 16%; p = 0.0002). Positivity for PD1 (n = 14/252, 5%) and PDL1 (n = 7/255, 3%) were rare, compared to reported in other tumor types. A trend towards higher PDL1 was observed in HER2+ mBC (8.3%; p = 0.0653). Ninety-three samples were analysed for WES with 17 genes found mutated in >3 samples (p Conclusions: This is the first study that assesses both immune and genomic landscapes in mBC. We observed that mBC dramatically differs from primary tumors, and is enriched in genes potentially involved in resistance mechanisms (ESR1, TSC1) or migration process (FRAS1, SCAPER). TILs, PD1, PDL1 are at very low frequency in metastatic lesions, except for Her2 + ++ mBC. Our results suggest that other immune suppressor networks are involved in mBC. Therefore, CD73, CD39 and FoxP3 are being analysed and will be presented. Disclosure: P.B. Robbins: Salary from Medimmune, Inc. All other authors have declared no conflicts of interest.

Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer

AIMSnTrastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab.nnnMETHODSnTrastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4xa0mgxa0kg(-1) loading dose followed by 5 weekly 2xa0mgxa0kg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate.nnnRESULTSnA total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1xa0l (23%), peripheral volume of distribution =1.3xa0l (38%), intercompartment clearance =0.36xa0lxa0day(-1) , with an elimination half-life of 11.8xa0days. Typical clearance was 0.22xa0lxa0day(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size.nnnCONCLUSIONSnIn non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied.

Loco-regional Control After Neo-adjuvant Chemotherapy and Conservative Treatment for Locally Advanced Breast Cancer Patients

Breast‐conserving treatment (BCT) has been validated for breast cancer patients receiving adjuvant chemotherapy. Our objective was to evaluate the difference in loco‐regional recurrence (LRR) rates between BCT and mastectomy in patients receiving radiation therapy after neo‐adjuvant chemotherapy (NCT). A retrospective data base was used to identify all patients with breast cancer undergoing NCT from 2002 to 2007. Patients with initial metastatic disease were excluded from this analysis. LRR was compared between those undergoing BCT and mastectomy. Individual variables associated with LRR were evaluated. Two hundred eighty‐four patients were included, 111 (39%) underwent BCT and 173 (61%) mastectomy. Almost all patients (99%) in both groups received postoperative radiation. Pathologic complete response was seen in 37 patients, of which 28 underwent BCT (p < 0.001). Patients receiving mastectomy had more invasive lobular carcinoma (p = 0.007) and a higher American Joint Committee on Cancer (AJCC) stage (p < 0.001) at diagnosis than those with BCT. At a median follow‐up of 6.3 years, the loco‐regional control rate was 91% (95% CI: 86–94%). The 10‐year LRR rate was similar in the BCT group (9.2% [95% CI: 4.9–16.7%]) and in the mastectomy group (10.7% [95% CI: 5.9–15.2%]; p = 0.8). Ten‐year overall survival (OS) rates (63% [95% CI: 46–79%] in the BCT group; 60% [95% CI: 47–73%] in the mastectomy group, p = 0.8) were not statistically different between the two patient populations. Multivariate analysis showed that AJCC stage ≥ III (HR: 2.6; 95% CI: 1.2–5.8; p = 0.02), negative PR (HR: 6; 95% CI: 1.2–30.6, p = 0.03), and number of positive lymph nodes ≥3 (HR: 2.5; 95% CI: 1.1–5.9; p = 0.03) were independent predictors of LRR. Ten‐year OS was similar in the BCT and in the mastectomy group (p = 0.1). The rate of LRR was low and did not significantly differ between the BCT and the mastectomy group after NCT. Randomized trials assessing whether mastectomy can be safely omitted in selected breast cancer patients (nonstage III tumors or those which do not require adjuvant hormone suppression) which respond to NCT are required.