Intrinsic Subtypes May Guide Treatment In Metastatic Breast Cancer, Early Colon Cancer

Gene-expression profiling of tumours may provide prognostic information in patients with metastatic breast cancer and those with stage II or III colon cancer

medwireNews: Two studies published in JAMA Oncology evaluate the role of intrinsic genomic subtypes for personalising the treatment of metastatic breast cancer or stage II/III colon cancer patients.

The first of these studies used data from the phase III EGF30008 trial in which postmenopausal women with hormone receptor-positive metastatic breast cancer and no previous treatment for metastatic disease were randomly allocated to receive letrozole together with either lapatinib or placebo.

Of the 821 tumour samples (85.7% primary tumour) included in the current study, the majority (80%) were HER2-negative.

In both HER2-negative and -positive patients, progression-free survival (PFS) varied significantly according to the intrinsic subtype, based on the PAM50 classifier comprising 50 genes. For instance, PFS was a median of 16.9 months for HER2-negative women with the luminal A subtype, and 11.0, 4.7 and 4.1 months for their counterparts with the luminal B, HER2-enriched and basal-like subtypes, respectively.

Similarly, overall survival also differed across the intrinsic subtypes, but the difference was significant only among women with HER2-negative disease.

Of note, HER2-negative patients with the HER2-enriched subtype – but none of the other subtypes –derived a significant benefit from the addition of lapatinib, with a median PFS of 6.49 versus 2.60 months for the placebo arm (hazard ratio [HR]=0.04).

Although the original study found that only HER2-positive patients had improved survival with lapatinib relative to placebo, our findings suggest that the addition of lapatinib to letrozole could be considered for HER2-enriched, HER2-negative patients, says the team led by Aleix Prat, from Vall d’Hebron Institute of Oncology in Barcelona, Spain.

Editorialist Mitchell Dowsett, from the Royal Marsden NHS Trust in London, UK, describes the approach as “unusual” and the findings as “provocative”, but says that we currently do not understand why patients with HER2-enriched, HER2-negative tumours benefit from added lapatinib.

“What are the molecular features that lead to such tumors being described as [HER2-enriched] if not HER2 itself?” he asks.

The second study – by Soonmyung Paik, from Yonsei University College of Medicine in Seoul, South Korea, and co-authors – used stored specimens from the NSABP C-07/NRG Oncology phase III trial that helped to establish the addition of oxaliplatin to fluorouracil and leucovorin as standard adjuvant therapy in early-stage colon cancer.

Using a modified panel of 72 genes (from a set of 295 initially tested genes), they approximately classified the 778 participants in the discovery cohort and the 825 in the validation cohort into one of five Colorectal Cancer Assigner (CRCA) subtypes: enterocyte, gobletlike, inflammatory, stemlike and transit amplifying.

Although stage III colon cancer patients with an enterocyte subtype had improved recurrence-free survival with the addition of oxaliplatin to fluorouracil plus leucovorin, this improvement was statistically significant only in the discovery cohort (HR=0.22; p=0.001), and not in the validation cohort (HR=0.53; p=0.14).

The researchers believe that “[l]ack of statistical power could be one reason for our failure to validate the enterocyte-oxaliplatin interaction”, and suggest further analysis in a cohort with greater power and a better panel of genes to delineate subtypes.

Writing in an accompanying editorial, Axel Grothey and Daniel Sargent, from Mayo Clinic in Rochester, Minnesota, USA, say the results are not “wholly surprising” as only a subset of genes was used to generate an approximate CRCA classification.

They add that although the study could not “clearly identify a molecular subgroup of patients with differential benefit from oxaliplatin, the study remains an important milestone in the field”, as it was the first assessment of a molecular subclassification based on comprehensive gene-expression profiling in the context of an adjuvant trial.

“We expect that future trials will use similar approaches in real time to subcategorize patients for specific interventions or at least use gene-expression profile information to stratify patients by risk group within clinical trials”, the commentators conclude.


Prat A , Cheang MCU, Galván P, et al. Prognostic value of intrinsic subtypes in hormone receptor–positive metastatic breast cancer treated with letrozole with or without lapatinib. JAMA Oncol 2016; Advance online publication 9 June. doi:10.1001/jamaoncol.2016.0922

Dowsett M. Intrinsic subgroups or individual biomarkers for predicting outcome of metastatic breast cancer? JAMA Oncol 2016; Advance online publication 9 June. doi:10.1001/jamaoncol.2016.0983

Song N, Pogue-Geile KL, Gavin PG, et al. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes. Secondary analysis of NSABP C-07/NRG Oncology randomized clinical trial. JAMA Oncol 2016; Advance online publication 6 June. doi:10.1001/jamaoncol.2016.2314

Grothey A, Sargent DJ. Adjuvant therapy for colon cancer. Small steps toward precision medicine. JAMA Oncol 2016; Advance online publication 6 June. doi:10.1001/jamaoncol.2016.2304

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