Background

Hormone-receptor (HR) positive, HER2-negative breast cancers make up about 60 % of the primary tumors. For these patients with 0 or up to 3 positive lymph nodes, the indication for chemotherapy is based on an accurate risk stratification. In this situation, conventional clinicopathological parameters are often not suitable for selecting those patients who would not benefit from adjuvant chemotherapy. The EndoPredict test combines a molecular signature with clinical risk factors such as tumor size and nodal status and stratifies patients into “low” or “high” risk groups and thereby improves decision-making. The EndoPredict test can predict the 10-year risk of distant metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment (Evidence level I-B).

Trial design

Patients with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes and an EndoPredict test within six months prior to inclusion are eligible. Primary objective is to show that patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone for at least 5 years have a 10-year distant metastasis-free survival of > 90 %. Secondary endpoints include distant metastasis-free survival, disease-free survival and overall survival in patients with EPclin “low” vs “high” risk. Also, the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors with respect to survival will also be assessed. Patients will be evaluated annually for 10 years regarding treatment compliance, recurrence, metastases, and survival. Start of accrual was in July 2018. At least 35 sites in Germany and one site in Switzerland will be active. Current data on enrollment will be reported. Survival data of patients who have been tested with EndoPredict are systematically assessed to prospectively prove that patients with a low risk classification by EndoPredict can safely forgo chemotherapy and be treated with endocrine therapy alone.

Clinical trial identification

NOGGO-B3 [18.12.2017].

Legal entity responsible for the study

North-Eastern German Society for Gynaecological Oncology e.V. (NOGGO e.V.).

Funding

Myriad Service GmbH.

Disclosure

C. Denkert: Patent holder: EP18209672 Patent application; Consulting fees: Fa, Teva, Novarits, Pfizer, Roche, Amgen, MSD, Daiichi, Celgene, AstraZeneca; Ownership interests: Sividon Diagnostics. M. Untch: Consulting fees: Linde. M. Kiechle: Speakers honorarium: Myriad, January 2018. All other authors have declared no conflicts of interest.

Background

Triple negative breast cancer (TNBC) is commonly associated with a poor prognosis. Platinum-compounds (P) and low dose oral cyclophosphamide (mCy) have showed activity in TNBC, exerting a direct cytotoxic and possibly immunomodulating activity. Neutrophil (ANC) to lymphocyte (ALC) ratio (NLR), derived NLR (ANC/[White blood cells − ANC]; dNLR), platelet to ALC ratio (PLR), and high lactate dehydrogenase (LDH) level have been proposed as measures of inflammatory/immunosuppressive status, associated with poor prognosis. The aim of this study is to evaluate these biomarkers in TNBC patients treated with P+mCy combination.

Methods

We report an exploratory retrospective analysis on cohort of advanced TNBC patients treated in a phase II trial with the combination of cisplatin (60 mg/mq Q3W) and mCy (50 mg QOD). Clinical data, complete blood count, and LDH level at baseline were collected. NLR>2.5, dLNR>3, PLR>200, and LDH>ULN were considered as significant. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model.

Results

A total of 47 patients treated from October 2011 to September 2015 were included. Median age was 55 years (26-77). More than 40% of the patients received the combination therapy as 2^nd line, while 36% was heavily pretreated (>2 lines). Objective response rate and 6-month disease control rate were 23.3% and 57.9%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.2 (2.9-5.4) and 12.7 (7.9-17.5) months, respectively. At univariate analysis, NLR>2.5 and PLR>200 were not associated with PFS and OS. dNLR>3 and LDH>ULN were associated with both reduced mPFS (1.8 vs 4.8 mo, HR 2.74, 95% CI 1.41-5.31, p=.003; 3.2 vs 5.8 mo, HR 2.19, 1.11-4.32, p=.023) and OS (4.2 vs 13.3 mo, HR 5.29, 2.22-12.6, p<.001; 5.7 vs 14.3 mo, HR 2.79, 1.26-6.15, p=.011). At multivariable Cox regression analysis, dNLR>3, but not LDH>ULN, was independently associated with PFS and OS.

Conclusions

dNLR confirmed a potential role to improve the selection of TNBC patients more likely to benefit from platinum-based and mCy regimens. Its validity, along with the implementation of new predictive biomarkers, warrants further studies for prospective validation.

Legal entity responsible for the study

Giuseppe Curigliano, MD PhD.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Predicting prognosis in metastatic HR+/HER2-negative disease might be of clinical value. Here, we developed and validated a prognostic biomarker in 765 patients (pts) recruited in 2 phase III trials evaluating endocrine-based therapies.

Methods

PAM50 and clinical data were available from 821 pts treated with letrozole+placebo/lapatinib in the first-line setting (EGF3008). Among them, 484 pts were selected based on HER2-negative disease and no prior endocrine therapy or relapse ≥6 months since tamoxifen discontinuation. To derive a prognostic model, the following variables were evaluated: 1) PAM50 subtypes, signatures and genes 2) ECOG, 4) visceral disease, 5) num. metastasis, 6) biopsy-type and 7) age. Using the variables, a progression-free survival (PFS) cox model was evaluated in 2/3 pts using Elastic Net (Monte Carlo CV). C-index of each model was estimated in 1/3 pts. The final model was tested in 261 pts treated with exemestane+placebo/everolimus (BOLERO2). PAM50 was performed in FFPE tumors (∼80% primary).

Results

In EGF3008, prognostic models that integrated PAM50 and clinical variables yielded superior C-index values compared to models with PAM50-only or clinical variables-only. The final model (PAM50MET) combined 21 variables, including 2 PAM50 subtypes, the Basal signature, 14 genes and 4 clinical variables. In EGF3008, the optimized cutpoint was associated with PFS (hazard ratio=0.41; p < 0.0001) and overall survival (OS; hazard ratio=0.41; p < 0.0001). In BOLERO2, PAM50MET score was associated with PFS (p = 0.004) and OS (p < 0.0001). Using the same cutpoint, PAM50MET-low was associated with better PFS (hazard ratio=0.72; p = 0.028) and OS (hazard ratio=0.51; p < 0.0001). The median PFS and OS in PAM50MET-low was 6.9 and 36.5 months compared to 5.2 and 23.4 months in PAM50MET-high.

Conclusions

PAM50MET could help identify pts with HR+/HER2-negative metastatic disease candidates, especially in the first-line setting, for endocrine therapy-only vs. endocrine therapy + CDK4/6 inhibitor vs. new treatment strategies. Further validation of PAM50MET in pivotal clinical trials that have evaluated endocrine-based therapies is justified.

Clinical trial identification

NCT00073528; NCT00863655.

Legal entity responsible for the study

Aleix Prat.

Funding

These trials was sponsored by Novartis Pharmaceuticals Corporation. This work was also supported by funds from the Spanish Society of Medical Oncology (to A.P.), Instituto de Salud Carlos III - PI13/01718 (to A.P.), Pas a Pas (to A.P.), Save the Mama (to A.P.), Instituto de Salud Carlos III - PI16/00904 (to A.P.), a Career Catalyst Grant (CCR13261208) from the Susan Komen Foundation (to A.P.), and Premio Jóven Investigador de la Fundación AstraZeneca (to A.P.).

Disclosure

A. Prat: Research funding: NanoString Technologies, GlaxoSmithKline, Susan G. Komen Foundation; Consulting/advisory relationship: NanoString Technologies, Novartis; Scientific advisory board: Novartis Pharmaceuticals Corporation, Pfizer, Roche. J.C. Brase: Employee: Novartis. S.R.D. Johnston: Consulting or advisory role: Eli Lilly, AstraZeneca, Puma Biotechnology; Speakers’ bureau: Pfizer, Novartis; Research funding: Pfizer (Inst). E.M. Ciruelos: Honoraria for consultancy and speaker: Lilly, Roche, Novartis, Pfizer. J.S. Parker: Co-inventor on patents related to the PAM50, licensed to NanoString Technologies, Inc. All other authors have declared no conflicts of interest.

Background

DD adjuvant CT is standard of care in high-risk early BC pts. However, the role of DD CT in HER2+ BC pts remains uncertain, particularly when T is administered. In this exploratory analysis of the GIM2 trial (Del Mastro et al, Lancet 2015), we investigated the efficacy of DD CT in the subgroup of HER2+ BC pts with or without subsequent exposure to T.

Methods

Using a 2x2 factorial design, the GIM2 trial randomized node-positive early BC pts to receive 4 cycles of (fluorouracil)epirubicin/cyclophosphamide (F)EC every 2 (DD) or every 3 (standard interval [SI]) weeks followed by 4 cycles of DD or SI paclitaxel (P). The same number of cycles (4 (F)EC and 4 P) and doses (FEC 600/90/600 mg/m2, P 175 mg/m2) were used in all treatment arms. After the approval of adjuvant T, protocol was amended in April 2006 to mandate use of T for 1 year after CT completion in all HER2+ pts. The efficacy of DD CT in terms of disease-free survival (DFS) and overall survival (OS) was compared between HER2+ pts with or without subsequent exposure to T and those with HER2-negative /HER2-unknown (HER2-/ukn) status.

Results

Out of 2,003 pts randomized to DD or SI CT in the GIM2 study, HER2 status was positive in 452 (22.6%) pts, negative in 1,243 (62.0%) and unknown in 308 (15.4%). Among 452 pts with HER2+ disease, T was administered to 132 (29.2%) pts. Overall median follow-up was 8.1 years (interquartile range: 7.0-9.3). There was no significant interaction between T therapy and the effect of DD CT, (p_interaction=0.603 for DFS and p_interaction=0.776 for OS); however, among pts treated with T, the effect of DD CT appeared to be smaller as shown in the table.

Table: 90O

Conclusions

In HER2+ early BC pts, DD adjuvant CT appears to have a role only in pts without subsequent exposure to T.

Clinical trial identification

NCT00433420.

Legal entity responsible for the study

GIM (Gruppo Italiano Mammella) Study Group.

Funding

Bristol-Myers Squibb, Pharmacia, and Dompè Biotec.

Disclosure

M. Lambertini: Advisory role: Teva; Speakers’ honoraria: Theramex. E. de Azambuja: Honoraria: Roche-Genentech; Research grants: Roche-Genentech (to the institution); Travel grants: Roche-Genentech, GlaxoSmithKline outside the submitted work. L. Del Mastro: Personal fees: Novartis Pharma AG, Roche-Genentech, Ipsen, AstraZeneca, Takeda, Eli Lilly outside the submitted work. All other authors have declared no conflicts of interest.

Background

HER2-targeting agents are standard of care for the treatment of HER2+ breast cancer (BC), but resistance inevitably occurs and the underlying molecular mechanisms remain poorly characterized. The comparison between mutational profiles of primary (treatment-naïve) and metastatic (who will mostly have received multiple courses of HER2-targeting agents) tumors can inform the search for resistance-inducing genetic alterations to be modeled in vitro and in vivo.

Methods

We analyzed the mutational spectrum of metastatic vs primary HER2+ BC by retrieving data from ERBB2-amplified cases in the MSKCC-IMPACT and the TCGA datasets, containing almost exclusively samples from metastatic sites and primary tumors, respectively. Multiple in vitro (HER2+ cell lines with stable RNA interference of candidate genes, 2D- and 3D-culturing) and in vivo models (NOD-SCID xenografts and the MMTV-neu transgenic mice) are used for validation.

Results

Mutations in NF1, TSC2 and HER2 were significantly enriched in metastatic cases. All are plausible mediators of resistance, being associated with signalling pathways downstream of HER2 or the HER2 receptor itself. NF1 in particular is a tumor suppressor gene which encodes a RAS-GTPase that negatively regulates Ras/MEK/ERK and PI3K/AKT/mTOR pathways. NF1 alterations were the most significant (Odds Ratio 11.7, p = 0.00018, FDR=0.23) and the most prevalent in metastatic cases (∼10%). As NF1 mutations lead to protein loss of function, we modeled their effect in vitro by RNA interference and found that it induces an increase in mTOR activation. Stably-interfered HER2+ cell lines will be used to explore synergistic drug combinations in vitro and in vivo.

Conclusions

We provide proof of concept that secondary resistance to anti-HER2 agents can be mapped to specific genetic alterations in a sizeable fraction of patients. Ongoing efforts are aimed at investigating if NF1 loss instructs HER2+ BC with a metastasis-promoting phenotype as well as metabolic and transcriptional changes.

Legal entity responsible for the study

European Institute of Oncology.

Funding

Fondazione IEO-CCM University of Milan.

Disclosure

G. Curigliano: Advisor: Roche, Pfizer, Novartis, Lilly. All other authors have declared no conflicts of interest.