Background

The irreversible pan-HER tyrosine kinase inhibitor neratinib had a significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized, phase 3 trial comparing neratinib + capecitabine (1500 mg, N+C) vs lapatinib + capecitabine (2000 mg, L+C) in 621 patients (pts) with HER2+ (either IHC3+ or IHC2+/FISH+) metastatic breast cancer (MBC) who received ≥2 prior HER2-directed regimens in the metastatic setting. Here we explore biomarker (PIK3CA or ERBB2 mutations, HER2 protein expression) associations with PFS changes.

Methods

PIK3CA and ERBB2 mutations were evaluated by next-generation sequencing on either primary (67.4%, 283/420) or metastatic/lymph node samples (32.6%, 137/420) and confirmed by ddPCR pending tissue availability. HER2 protein expression was evaluated by central IHC, H-score, and HERmark. Hazard ratios (95% CI) for subgroups were estimated using unstratified Cox proportional hazards model.

Results

PIK3CA and ERBB2 mutations were detected at incidences of 35.0% (148/420) and 6.2% (26/420), respectively. PIK3CA mutations were associated with decreased PFS (wt vs mut: HR=0.81; 95% CI 0.64–1.02; p=0.077). ERBB2 mutation trended with better PFS, but sample size was limited (wt vs mut: HR=1.68, CI 0.97–3.29, p=0.086). Higher HER2 protein expression was prognostic of increased PFS when treatment arms were grouped (IHC3+ vs 2+: HR=0.67, CI 0.54–0.82, p<0.001; H-score above vs below median HR=0.77, CI 0.63–0.92, p=0.005; HERmark positive vs equivocal or negative HR=0.71, CI 0.52–0.98, p=0.006). Pts whose tumors had higher HER2 protein expression evaluated by any of the three methods appeared to have derived consistent benefit from N+C vs L+C (HER2 IHC3+: HR=0.64, CI 0.51–0.81, p<0.001; H-score ≥median (240): HR=0.54, CI 0.41–0.72, p<0.001; HERmark positive: HR=0.65, CI 0.50– 0.84, p<0.001).

Conclusions

PIK3CA mutations associate with decreased PFS for pts enrolled in the NALA trial. Higher HER2 protein expression associates with increased PFS in the overall study population, and a greater benefit from N+C vs. L+C.

Clinical trial identification

NCT01808573.

Editorial acknowledgement

Lee Miller, Miller Medical Communications Ltd.

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

C. Saura: Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eisai; Advisory/Consultancy: Genomic; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Synthon; Advisory/Consultancy: Piqur Therapeutics; Advisory/Consultancy: Sanofi. A. Vivancos: Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bayer. H. Wildiers: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Amgen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Vifor Pharma; Advisory/Consultancy: Celldex therapeutics; Advisory/Consultancy: Janssen-CILAG; Advisory/Consultancy: TRM Oncology; Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: ORION corporation. A.M. Brufsky: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Agendia; Advisory/Consultancy: Celgene; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bayer; Advisory/Consultancy: Lilly; Advisory/Consultancy: bioTheranostics; Advisory/Consultancy: NanoString Technologies; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Puma Biotechnology Inc. M. Oliveira: Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: GlaxoSmithKline; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grunenthal. S. Waters: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche. B. Moy: Honoraria (self): Medscape Education; Spouse/Financial dependant: Motus GI. S-B. Kim: Advisory/Consultancy: Enzychem; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate; Advisory/Consultancy: Beigene; Research grant/Funding (institution): Sanofi-Genzyme; Research grant/Funding (institution): Dongkook. W.J. Gradishar: Advisory/Consultancy: Genentech/Roche. J. Bebchuk: Full/Part-time employment: Puma Biotechnology Inc. K. Keyvanjah: Full/Part-time employment: Puma Biotechnology Inc. A.S. Lalani: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. L.D. Eli: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. S. Delaloge: Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Pfizer; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Novartis; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Puma Biotechnology Inc.; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: AstraZeneca; Honoraria (self), Advisory/Consultancy: Lilly; Advisory/Consultancy: Orion; Honoraria (self), Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.

Background

Recently, HER3 has received attention as new anti-HER3 antibody-drug conjugates (e.g. U3-1402) are showing activity in BC. The most common method to determine HER3 expression is immunohistochemistry (IHC)-based assays. However, technical limitations exist when using IHC, such as different sensitivities of the antibodies and its subjectivity in scoring and cut-off determination. To overcome those limitations, we developed an mRNA-based ERBB3 expression assay using FFPE BC tissues and the Nanostring nCounter platform.

Methods

1,580 FFPE primary BC samples representing all IHC-based subtypes, nCounter-based PAM50 subtypes, and ERBB3 expression were analyzed. Results were compared to an independent cohort, METABRIC dataset, which includes 1,943 BC samples analyzed by the Illumina HT 12 IDATS platform.

Results

Among 1,580 samples, 65% were hormonal receptor positive (HR+) and 18% were HER2+. IHC subtype distribution was as follows: 52% HR+/HER2-, 14% HER2+/HR+, 5% HER2+/HR- and 29% triple-negative (TNBC). PAM50 distribution was: 28% Luminal A, 20% Luminal B, 14% HER2-enriched, 29% Basal-like and 9% Normal-like. The range of ERBB3 mRNA expression had an 18.6-fold difference (i.e. from the lowest to the highest ERBB3 value) and the inter-quartile range was 1.5 (in log2), which equals to a difference in expression of 2.9-fold. Overall, HR+/HER2- or PAM50 Luminal A/B subtypes showed the highest expression compared to the other subtypes. The table shows the proportion in our dataset and METABRIC using quartiles and correlation coefficients (CC). Interestingly, the CC of the proportions between the 2 datasets were very similar. Table: 2O

Comparison of the distribution of tumor samples according to ERBB3 mRNA expression in our in-house (IH) nCounter-based dataset versus METABRIC (MB) dataset. Proportions (%) of tumor samples within each quartile (Q) based on IHC subtype and correlation coefficients between both datasets.

Conclusions

High ERBB3 mRNA gene expression is observed across all subtypes of BC, although it predominates in HR+/HER2- disease. The assay using FFPE tissues is feasible and reliable. The predictive value of this biomarker will be prospectively tested in the upcoming SOLTI-1805 TOT-HER3 window trial using the U3-1402 anti-HER3 antibody-drug conjugate.

Legal entity responsible for the study

SOLTI Breast Cancer Group.

Funding

Pas a Pas (AP), Save the Mama (AP). Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2018 (TP).

Disclosure

M. Oliveira: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips Healthcare; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Immunomedics; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): GSK; Research grant/Funding (institution): Boehringer-Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Zenith Epigenetics; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grünenthal; Travel/Accommodation/Expenses: Eisai. E.M. Ciruelos: Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. M. Bellet Ezquerra: Honoraria (institution), Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celgene; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. J. Gavila Gregori: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: MSD Oncology. S. Pernas Simon: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Polyphor; Advisory/Consultancy: TFS. M.J. Vidal: Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Daiichi Sankyo. M. Margeli Vila: Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Kern; Research grant/Funding (self): Celgene; Research grant/Funding (self): Kern. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString Technologies. A. Prat: Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: NanoString Technologies; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self): MSD Oncology; Honoraria (self): Lilly; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background

A subcutaneous fixed-dose combination of P + H (PH FDC SC) may offer pts less invasive, faster administration vs intravenous P + H (PH IV). PHranceSCa is an open-label, randomised cross-over study evaluating pt preference and satisfaction with PH FDC SC vs PH IV.

Methods

Pts with histologically confirmed, HER2+ eBC who completed neoadjuvant therapy with P + H + chemotherapy and had surgery are enrolled and 1:1 randomised to Group A: 3 cycles of PH IV every 3 weeks (q3w) (P: 840 mg loading dose, 420 mg maintenance; H: 8 mg/kg loading; 6 mg/kg maintenance) then 3 cycles of PH FDC SC q3w (loading: 1200 mg P, 600 mg H; maintenance: 600 mg P, 600 mg H); or Group B: 3 cycles of PH FDC SC q3w then 3 cycles of PH IV q3w. Pts then choose PH FDC SC or PH IV to complete anti-HER2 therapy (up to 18 cycles). The primary objective is to evaluate patient preference for PH FDC SC.

Results

At clinical cut-off (19-08-19), 118 patients were randomised (Group A, n = 56; Group B, n = 62). All were female; median age was 49 years. 42/51 pts (82%; 95% CI 69–92%) who completed the cross-over therapy preferred PH FDC SC. Main reasons for PH FDC SC preference were “less time in clinic” (n = 38) and “more comfortable therapy administration” (n = 22). 46/51 (90%) pts were “very satisfied” or “satisfied” with PH FDC SC vs 34/51 (67%) with PH IV. 84% pts chose PH FDC SC to complete their therapy. 81/116 pts had ≥1 adverse event (AE), 1 had a serious AE (PH IV; pyrexia) and 5 had a Grade 3 AE (PH FDC SC, n = 3: ejection fraction [EF] decrease, diarrhoea, device-related infection; PH IV, n = 2: EF decrease, lymphopenia); there were no deaths and no AEs led to study discontinuation. 16/116 (13.8%) pts had diarrhoea, mainly low grade. Systemic administration-related reaction rates were 2/116 (1.7%) for PH FDC SC and 3/116 (2.6%) for PH IV. 21/116 (18.1%) pts had local injection site reactions; there were no local infusion-related reactions.

Conclusions

In the PHranceSCa interim analysis, 82% (95% CI 69–92%) of pts preferred PH FDC SC. PH FDC SC was generally well tolerated; the safety profile was consistent with PH IV and no new safety signals were seen.

Clinical trial identification

NCT03674112.

Editorial acknowledgement

Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd.

Legal entity responsible for the study

F. Hoffman-La Roche.

Funding

F. Hoffman-La Roche.

Disclosure

J. O'Shaughnessy: Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Agendia; Honoraria (self), Advisory/Consultancy: Amgen Biotechnology; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Celgene Corporation; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Genentech; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: GRAIL; Honoraria (self), Advisory/Consultancy: Immunomedics; Honoraria (self), Advisory/Consultancy: Heron Therapeutics; Honoraria (self), Advisory/Consultancy: Ipsen Biopharmaceuticals; Honoraria (self), Advisory/Consultancy: Jounce Therapeutics; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Myriad; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Ondonate Therapeutics; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Puma Biotechnology; Honoraria (self), Advisory/Consultancy: Prime Oncology; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Syndax Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. S.P. Sousa: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Tesaro; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca/MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. J. Cruz: Honoraria (self), Advisory/Consultancy: Glaxo; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: PharmaMar; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. L.J. Fallowfield: Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Genomic Health; Honoraria (self): NanoString; Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. P. Auvinen: Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. C. Pulido: Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. A. Cvetanovic: Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. S. Wilks: Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. L. Ribeiro: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Personal Education: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. M. Burotto: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. D. Klingbiel: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. D. Messeri: Full/Part-time employment, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. A. Alexandrou: Shareholder/Stockholder/Stock options: Pfizer; Full/Part-time employment, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. P. Trask: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech Inc; Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. J. Fredriksson: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd. L. Stamatovic: Non-remunerated activity/ies, Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, PhD, of Health Interactions, was provided by F. Hoffman-La Roche Ltd.

Background

In TNBC, the IM signature is highly enriched in immune cell markers and signaling which likely represents gene expression from both the tumor cells and infiltrating lymphocytes. High sTIL is independently associated with improved pCR rates in TNBC. The association between the IM subtype and sTIL in predicting pCR is not known.

Methods

Pretreatment core biopsies from 181 patients with early-stage TNBC enrolled on the ARTEMIS trial (NCT02276443) were evaluated for sTIL by H&E and Vanderbilt subtype using Affymetrix arrays and TNBCtype. sTIL was graded as low (<10%), moderate (10-30%) and high (>30%) using cut-points previously established to correlate with pCR. We calculated a point estimate and 95% confidence interval for the probability that a subject with given IM and TIL status will achieve pCR.

Results

The IM subtype was identified in fewer TNBCs with low or moderate sTIL (4 and 27%, respectively) than in those with high sTIL (62%, p<0.05). Independently, IM subtype and high sTIL subgroups achieved pCR at similar rates (62% and 76% respectively). We observed the largest difference in pCR rates between IM and non-IM subtype patients in the Moderate sTIL group. (58% vs 33%, p=0.051). Table: 98O

sTIL and pCR rates according to IM status

Conclusions

High TIL and IM subtype are associated with similar rates of pCR and the addition of the IM signature to sTIL high or sTIL low TNBCs did not impact prediction of pCR. In patients with moderate TIL, the IM subtype was associated with higher rates of pCR (58%) as compared to other subtypes (33%). Larger numbers of patients are needed to confirm the predictive value of the IM signature in TIL moderate TNBC.

Legal entity responsible for the study

The authors.

Funding

MD Anderson Moon Shots Program, CPRIT Multi-Investigator Research Award (MIRA).

Disclosure

B. Lim: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen. B. Arun: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Invitae. S. Moulder: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background

Activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT1 oncogenes, and mutations in the PTEN tumour suppressor gene, occur in 40–50% of oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC). We assessed phosphatidylinositol 3-kinase (PI3K) pathway mutations in circulating tumour DNA (ctDNA) from responding patients in SANDPIPER (NCT02340221), a phase III study of taselisib (PI3K inhibitor) or placebo with fulvestrant in ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC.

Methods

Baseline and study discontinuation ctDNA samples were analyzed from 99 patients in SANDPIPER who had baseline tumour PI3KCA mutations (cobas® PIK3CA Mutation Test, Roche Molecular Systems) and had experienced a response or an extended progression-free survival with tumour shrinkage. Samples were assessed by next-generation sequencing (FoundationOne® Liquid assay, Foundation Medicine) using a proprietary analysis pipeline.

Results

85/99 paired samples were evaluable for ctDNA sequencing, with 54 (63.5%) and 85 (100%) PIK3CA mutation-positive by baseline plasma and tissue, respectively. Of the 85 mutations newly detected at study discontinuation (i.e. absent at baseline), the most common were ESR1 (21), TP53 (10), PIK3CA (8), PTEN (8), and ERBB2 (5). Activating AKT1 and loss of function PTEN mutations were identified in the taselisib arm only.

Conclusions

Detection of AKT1 and PTEN mutations in the PI3K pathway within this population suggests possible resistance mechanisms following treatment with PI3K inhibitors. The recent approval of alpelisib in hormone-receptor (HR)-positive, PIK3CA-mutant BC, in addition to the development of novel AKT inhibitors in HR-positive, HER2-negative BC, highlight the importance of understanding changes in the PI3K pathway following treatment with inhibitors.

Clinical trial identification

GO29058/NCT02340221; 24 Jun 2018.

Editorial acknowledgement

Support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

W. Jacot: Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly France; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Chugai Pharma; Travel/Accommodation/Expenses: GlaxoSmithKline; Travel/Accommodation/Expenses: Pierre Fabre; Travel/Accommodation/Expenses: Sanofi Aventis. H.M. Savage: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech, Inc. S. Dent: Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Honoraria (self), Research grant/Funding (self): Novartis Canada. J. Cortés: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Shareholder/Stockholder/Stock options: MedSIR; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Cellestia; Advisory/Consultancy: Biothera Pharmaceuticals; Advisory/Consultancy: Merus; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Erytech; Advisory/Consultancy: Athenex; Advisory/Consultancy: Polyphor; Advisory/Consultancy: Servier; Advisory/Consultancy: GSK; Research grant/Funding (institution): Ariad Pharmaceuticals; Research grant/Funding (institution): Baxalta GmbH/Servier Affaires; Research grant/Funding (institution): Bayer Healthcare; Research grant/Funding (institution): Guardant Health; Research grant/Funding (institution): Piqur Therapeutics; Research grant/Funding (institution): Puma C; Research grant/Funding (institution): Queen Mary University of London; Research grant/Funding (institution): SeaGen. Y-H. Im: Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd. V.C. Dieras: Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Merck Sharp and Dohme. N. Harbeck: Honoraria (self), Non-remunerated activity/ies, support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Honoraria (self): Novartis. I.E. Krop: Honoraria (self), Research grant/Funding (institution), Non-remunerated activity/ies, support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Honoraria (self), Research grant/Funding (institution): Genentech, Inc.; Research grant/Funding (institution): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Daiichi Sankyo; Honoraria (self): Macrogenics; Honoraria (self): Context Therapeutics; Honoraria (self): Taiho Oncology; Honoraria (self): Celltrion. J. Chen: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc. E. Sokol: Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. F. Schimmoller: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc.; Shareholder/Stockholder/Stock options, Patent or intellectual property interests: Exelixis; Shareholder/Stockholder/Stock options: Teva. J. Hsu: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc. M. De Laurentiis: Honoraria (self), Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Celgene; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Amgen; Honoraria (self): MSD. T.R. Wilson: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Support for third-party writing assistance for this abstract: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc.

Background

Breast cancer (BC) may recur many years after primary diagnosis. We investigated the incidence of late breast cancer recurrence (BCR) (>= 10 years after primary surgery) and identified potential associations between clinico-pathological factors at baseline and late BCR.

Methods

Using the Danish Breast Cancer Group’s (DBCG) database we identified all women with incident stage I-III operable BC diagnosed during 1987-2002, who were alive and without a recurrence or new primary cancer 10 years after diagnosis. We derived an algorithm to identify late BCR using Danish population-based registries. Follow-up began 10 years after primary surgery date and continued until late BCR, death, emigration, second cancer or 31/12/2013. Crude incidence rates (IRs) per 1,000 person-years (PY) and cumulative incidence proportions (CIPs) for late BCR were calculated by patient- and tumor characteristics at baseline. Cox regression models were used to calculate hazard ratios (HRs), accounting for competing risks. The HRs were adjusted for tumor- and patient characteristics.

Results

18,117 women of 31,528 (57%) reached year 10 without BC recurrence, a contralateral breast cancer or other primary cancer, and were followed for a total of 106,602 PY with a median follow-up of 4.9 years (IQR; 2.4-8.7). Of these 10-year survivors, 1,763 developed late BCR corresponding to an IR of 16.5 (95% CI, 15.8-17.3) per 1,000 PY and a CIP of 15% maximum 27 years after primary diagnosis. The CIP was higher among patients with estrogen receptor (ER)⁺ tumors, stage III disease and high nodal status. We found an adjusted HR of 3.0 (95% CI, 2.47-3.55) for patients with 4 or more positive lymph nodes versus patients with no lymph node involvement, an adjusted HR of 1.85 (95% CI, 1.59-2.15) for patients with stage III disease versus stage I disease and an adjusted HR of 0.57 (95% CI, 0.45-0.72) for patients with an ER^- tumor versus patients with an ER⁺ tumor.

Conclusions

Our findings suggest that women with breast cancer can remain disease-free for at least ten years, but recurrences continue to occur from 10 to 27 years after primary diagnosis. Baseline tumor characteristics such as lymph node status, stage, and ER receptor status seems to be associated with late breast cancer recurrence.

Legal entity responsible for the study

Aarhus University.

Funding

The Danish Cancer Society.

Disclosure

B. Ejlertsen: Research grant/Funding (institution), Research funding to my institution from NanoString, Roche, Novartis, and Oncology Venture: Rigshospitalet, Copenhagen University Hospital. All other authors have declared no conflicts of interest.