by ecancer reporter Clare Sansom

Meetings in the IIAR series have always featured a number of sessions covering recent advances in the treatment of specific types of cancer.

Two of these sessions held on the final day of the 2014 meeting, Friday 10 October, covered breast cancer and haematological malignancies.

The haematological session began with a wide-ranging overview of the current treatment options for chronic myeloid leukaemia (CML) by Binay Shah of St Joseph Regional Medical Center, Lewiston, Idaho, USA.

About 15-20% of adults diagnosed with leukaemia will have CML; the median age at diagnosis is 55, with most patients presenting in the chronic phase of the disease.

On the cellular level, it is almost always characterised by the so-called “Philadelphia Chromosome” translocation between chromosomes 9 and 22, resulting in the aberrant tyrosine kinase Bcr-Abl.

The prognosis for CML patients improved dramatically in the early 2000s when the first inhibitor of this kinase, imatinib, entered clinical use.

Shah described several landmark clinical trials that led to the addition of two further tyrosine kinase inhibitors, dasatinib and nilotinib, to the range of first-line therapies available for this condition.

The choice of initial therapy remains unclear: dasatinib and nilotibib produce better cytological responses in most patients than imatinib, but are less well tolerated, and imatinib is also cheaper.

The two newer drugs are therefore probably better initial choices unless a patient has certain co-morbidities or unless cost is a serious concern.

Patients can be switched to a second kinase inhibitor if they fail the first; those who carry the T315 mutation and those who fail two can now be offered a promising new drug, the protein translation inhibitor omacetaxine.

Tamar Tadmore from Bnai-Zion Medical Center, Haifa, Israel, described the aetiology and treatment of Richter’s syndrome, a rare complication of B-cell chronic lymphocytic leukaemia (CLL).

Most patients diagnosed with this condition experience long remissions, but in about 5% of patients the leukaemia cells become transformed into an aggressive lymphoma: this is Richter’s syndrome, and it carries a poor prognosis.

The most common transformation is into a diffuse large B cell lymphoma (DLBCL).

A small minority of cases involve transformation into Hodgkin’s lymphoma, in which case the disease is known as Hodgkin’s variant Richter syndrome (HvRS).

Diffuse large B cell lymphoma or Hodgkin’s lymphoma can also develop separately in patients with CLL, and this has a very similar aetiology and prognosis to so-called “true” Richter syndrome.

Tadmore described a series of patients 119 diagnosed with Richter syndrome at 12 centres within Israel between 1996 and 2010.

Sixty percent of the patients were men, and 89% were of Jewish origin (compared to 75% of the population of Israel as a whole).

Patients with DLBCL have a worse prognosis than those with HvRS; Tadmore found the 5-year survival rates of the two cohorts to be 8 months and 39.5 months following diagnosis of Richter syndrome respectively.

Both Richter-related DLBCL and HvRS are treated with the same chemotherapy regimens as diffuse large B cell lymphoma and Hodgkin’s lymphoma, but there is evidence that at least some patients with DLBCL will benefit from the addition of a monoclonal antibody, particularly rituximab.

Cecilia Evangelisti from the University of Bologna, Italy described the potential of drugs targeting the sphingolipid pathway for treating T-cell acute lymphoblastic leukaemia (T-ALL).

This type of the disease accounts for about 15% of paediatric and 25% of adult leukaemia cases worldwide; many patients can be relatively well treated with drugs, but novel, less toxic therapies are still needed.

A signalling pathway involving a class of membrane lipids known as sphingolipids is known to be crucial in determining the balance between cell death and cell survival.

The sphingosine kinases SK1 and SK2 play important roles in this pathway by phosphorylating sphingosine to its 1-phosphate (S1P).

Evangelisti explained that both T-ALL cell lines and cells taken from patients with this condition undergo apoptosis when treated with a non-selective SK1/SK2 inhibitor.

However, a minority of these cells become resistant to the inhibitor through activating the endoplasmic reticulum stress / unfolded protein response, which leads to a pro-survival autophagy.

In contrast, treating the same cell lines and primary cells with the specific SK2 inhibitor ROMe induce uniform cell death through autophagy.

She suggested that specific inhibitors of SK2 might be potential therapies for this type of leukaemia.

Breast cancer is as heterogeneous a disease as chronic or acute leukaemia, and the molecular profile of a patient’s cancer may change over time.

In a session devoted to the aetiology and therapy of all types of breast cancer, Marius Raica from Research Center Timisoara, Timisoara, Romania described his work in determining the molecular profiles of primary breast tumours and corresponding lymph node metastases.

Breast tumours are currently classified into five main molecular subtypes – luminal A, luminal B, basal, HER2 positive and “other” (or sometimes “normal-like”) – based on expression levels of molecular markers including, but not restricted to, the oestrogen, progesterone and HER2 receptors.

Until now, most measurements of these expression patterns have been made in primary tumours only.

Raica described experiments to stratify both primary tumours and matched lymph node metastases and to determine the extent to which both the expression pattern and the derived subtype changed or remained stable in individual patients.

He found changes in expression pattern that led to a re-classification in about a quarter of all patients tested.

The HER2 subtype was the most stable, with few conversions between HER2 status in primary tumours and a different subtype in the lymph node metastases.

In contrast, the luminal A subtype was the least stable, with many luminal A primary tumours being re-classified as luminal B or even basal in the metastases.

He concluded that a re-evaluation of the molecular profile of lymph node metastases may be useful both in modifying the therapeutic strategy for a subset of current patients, and in identifying new targets and potential therapies.

Further talks in the same session discussed the role of oestrogen blocking and tailored chemotherapy in pre-menopausal patients with breast tumours at high risk of recurrence, and the use of polymorphisms in the gene CYP19A1, which codes for aromatase, in predicting the outcome for post-menopausal patients treated with the aromatase inhibitor letrozole.

I would like to dedicate this post, and my other posts in this series, to Dora Kemp, a colleague of my husband at Cambridge University, UK, who lost her battle with acute leukaemia on 3 October 2014 – Dr Clare Sansom