by ecancer reporter Clare Sansom

Since 2005, the American Society of Clinical Oncology (ASCO) has published an annual report detailing the main advances made in clinical cancer research during the last year.

The 2015 report has now been published simultaneously in the Journal of Clinical Oncology and on the ASCO website, CancerProgress.net.

As this is the report’s tenth anniversary year, it featured, besides descriptions of important research developments, a review of the last decade in clinical oncology and a look ahead to the next one.

In general, the report was forward-looking and optimistic, stressing the enormous advances that have been made and those still on the horizon, but one note of caution was introduced into the introduction: a serious concern about research funding.

The report’s authors highlighted a decline in US government funding for medical research since about 2003 that, they said, both threatened the country’s position as a world leader and impeded progress more generally; they called on Congress to commit to higher levels of funding.

The report also introduced a new feature, ASCO’s Advance of the Year: in 2015, which was the transformation of the treatment of chronic lymphocytic leukaemia (CLL) by the introduction of four new drugs.

The President of ASCO, Peter Paul Yu of the Palo Alto Medical Foundation, California, USA, highlighted this choice in his Preface by referring to the lack of previous options for the treatment of this disease, which is the most common type of leukaemia to affect adults.

Before 2014, the only drugs available for CLL were toxic and difficult for the mainly elderly patient population to tolerate.

The recently licensed drugs that have transformed the options available for these patients are two immunotherapies, obinutuzumab and ofatumumab, and two tyrosine kinase inhibitors, ibrutinib and idelalisib.

Both obinutuzumab and ofatumumab have been licensed for the treatment of newly diagnosed CLL in combination with the standard chemotherapy drug chlorambucil.

They have been shown in clinical trials to greatly increase the average time to disease progression.

In contrast, the newly approved kinase inhibitors are both licensed in advanced and treatment-resistant CLL.

Ibrutinib inhibits Bruton’s tyrosine kinase, which plays a key role in the development of B cells; it has been approved for CLL patients who bear a particular chromosomal alteration, 17p deletion, which is associated with poor prognosis.

Idelalisib is a selective inhibitor of one isoform of phosphoinositide 3-kinase (PI3Kδ) and it is licensed for advanced CLL in combination with a monoclonal antibody, rituximab.

The main part of the report was divided into sections dealing with advances in prevention and screening; treatment; patient care; and tumour biology.

Following a short introduction highlighting the importance of public health measures, the section on cancer screening and prevention described two major advances: anastrazole as a chemo-preventative for post-menopausal breast cancer, and screening for lung cancer with low-dose computed tomography (CT).

Anastrazole is an inhibitor of the enzyme aromatase, which catalyses a key step in the bisynthesis of oestrogen, and it is already licensed for the treatment of oestrogen dependent (ER positive) breast cancer.

A large study of women considered to be of high risk of breast cancer has now shown that this drug is also effective in preventing the disease after the menopause.

Out of about 4,000 women with risk factors such as high breast density, benign breast disease or a family history of breast cancer enrolled onto this trial, about 2% of the women who received anastrazole developed breast cancer during 5 years compared to 4% of women receiving a placebo.

The drug was shown to be at least as effective as the chemo-preventative drugs that are already available and to be extremely safe, with very few severe adverse effects: in particular, there was no increase in either of the two known serious side effects of the competitor drug tamoxifen, blood clots and endometrial cancer.

Most types of lung cancer have extremely poor prognoses, and one of the many reasons for this is the difficulty in detecting this disease at an early stage, where it can be treated relatively easily.

Smoking is by far the most important risk factor for the development of lung cancer, and most research into lung cancer screening is conducted in current or recent smokers.

Several clinical trials have suggested that screening with low-dose CT can prevent about 20% more deaths from lung cancer compared to the traditional chest X-ray.

Guidelines published in March 2014 suggest that present and recent heavy smokers aged between 55 and 80 should be screened for lung cancer annually using this technique.

However, analysis of the risks and benefits of screening has shown that screening with CT has a high false positive rate with about 96% of the observed abnormalities being benign lesions.

This research supports the targeting of screening to those individuals who are considered to be at the highest risk of developing lung cancer.

It has also been shown that lung cancer screening increases smoking cessation rates, which is another key advantage of this intervention.

The highlighted advances in cancer treatment were further divided into categories: combination therapies; targeted therapies; immunotherapies; and progress in the treatment of rare cancers.

Under the heading of combination therapies the report’s authors highlighted a combination of chemotherapy with radiotherapy in low-grade gliomas that extends patients’ lifespan by over 5 years compared to radiotherapy alone, and a combination of chemotherapy with hormone therapy for advanced prostate cancer.

The targeted cancer therapies described included treatment options for non-small cell lung cancer with specific mutations and two intractable tumour types, advanced stomach cancer and radio-iodine resistant differentiated thyroid cancer.

Two experimental drugs that target a mutated form of EGFR, AZD9291 and CO-1686, have shown promising results in early clinical trials, and as these compounds inhibit only the mutated kinase they have little effect on the wild type EGFR in normal cells and so few serious side effects.

Last year also saw the licensing of ceritinib for NSCLC; this specific inhibitor of the kinase ALK is effective in patients with mutations in this kinase who are unable to tolerate crizotinib.

The FDA also recently approved ramucirumab, a monoclonal antibody that acts as an angiogenesis inhibitor (i.e. blocks the blood supply to the tumour) for the treatment of advanced stomach cancers including those located in the region where the oesophagus joins the stomach.

This is the first angiogenesis inhibitor to have been shown to be effective as a standalone treatment of a gastro-intestinal tumour.

The final treatment advance highlighted in this section was lenvatinib, which inhibits several different kinases activated in tumours and is effective in treating thyroid tumours that are resistant to the commonly curative radio-iodine therapy.

Interventions that come under the heading of patient care are designed to improve the quality of life of cancer patients, and therefore may include policy initiatives as well as scientific advances.

The ASCO report highlighted three very different approaches in this area.

One of these was a large study that showed that patients who received palliative care soon after a diagnosis of advanced cancer had improved physical, mental and emotional wellbeing compared to those who received only treatments aimed at controlling the tumour at this stage.

Two studies have shown that administering a drug such as goserelin that potentiates the gonadotropin releasing hormone, temporarily preventing the production of oestrogen, can prevent early menopause in breast cancer patients allowing more to give birth following treatment.

Ways of highlighting, and hopefully reducing, inequalities in access to treatment and in cancer outcomes for minorities were also included under this heading.

The report also presented some important advances in understanding the biology and genetics of tumours.

One large study highlighted involved the genomic analysis of about 7,000 tumours that divided them into 20 groups termed mutational signatures based on combinations of mutations.

Some of these signatures seemed to be associated with known cancer triggers such as tobacco and ultra-violet light, and others with the age of the patient at diagnosis.

Another study showed that tumours in different organs could have similar genetic or molecular profiles, suggesting that it might be more effective to target therapies to the mutational signatures of tumours than to their type. 

Prostate tumours that carry a specific mutation in the androgen receptor that produces a truncated form of the protein are known to be resistant to the anti-androgens enzalutamide and abiraterone, which are commonly used to treat this cancer.

It has now been shown that it is possible to detect this mutation in circulating tumour cells through a simple blood test, and that this test can predict which patients will show resistance to these drugs.

Two novel studies in mice have suggested that bacteria in the gut may play beneficial roles in protecting against cancer and in potentiating the activity of some anti-tumour agents.

One of these showed that both immunotherapy drugs and oxaliplatin were less effective in treating mouse tumours if the mice had also been treated with antibiotics to eradicate their gut bacteria; the other that antibiotic-treated mice produced tumours that were resistant to a drug that boosts the immune response to cancer, cyclophosphamide,.

Two further sections of the report looked back at the decade since the publication of the first edition of Clincal Cancer Advances and forward to developments that could be expected in the next.

The review of the last ten years highlighted the rapid development of targeted therapies, particularly but not only kinase inhibitors; the importance of the cancer genome projects; and the increasing role of immunotherapy in treating cancer.

More than sixty new drugs for cancer were approved by the FDA in the ten years from 2005-2014, and a roughly equivalent number were licensed for further indications.

These and other advances have improved the survival chances for patients with a wide variety of tumours.

There have also been advances in palliative care, reducing side effects, and in screening and prevention: the most significant under the last heading probably being the development of HPV vaccines and tests for HPV infection as strategies for the prevention and early detection of cervical cancer.

Looking forward another ten years, the report’s authors suggested that future advances in cancer treatment would be likely to come from even more sophisticated genomics technology; targeting cancer stem cells; the use of “liquid biopsies” to detect and diagnose cancers from circulating tumour cells and tumour DNA in the blood; and, perhaps more controversially, nano-medicine.

They also highlighted the importance of IT and “big data” in cancer research and treatment, stressing the value of integrating data from multiple sources and recruiting more patients into clinical trials.

Reference

Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress against Cancer. Journal of Clinical Oncology, published online ahead of print 20 January 2015.