J. De Grève MD, PhD

Moving beyond the single agent targeting of activated pathways in cancer and emerging therapeutic targets in rare cancers

The ECC meeting is mostly focused on clinical results and some translational medicine. Nevertheless a couple of interesting developmental topics were presented.

Identification of primary drivers in all cancer types is moving along and treatments that match these genotypes are available or in development. One of the next challenges is to increase the initial efficacy of these treatments and overcoming secondary resistance. Indeed, all cancers treated with targeted agents, despite impressive results, ultimately become resistant due to secondary resistance mechanisms. In addition there is also something as “innate” resistance: the primary treatments do not achieve a maximal pathway shutdown and therapeutic efficacy. This is in part due to the pharmacological limitations of small molecules and monoclonal antibodies in the inhibition of the pathways they target. Hitting the same target with specific siRNA’s is generally more effective in shutting down the activated pathway. In addition, this innate resistance is also due to functional responsiveness of the cells that results in the activation of alternative pathways that dampen the effect of the primary treatment. Identification of these functional resistance mechanisms is important, as they would be candidate co-targets for primary targeted therapies. Another major void in our cancer armamentarium is the therapeutic exploitation of recessive cancer genes and tumor suppressor genes.

(BELG J MED ONCOL 2015;9:260–62)

Highlights in targeted therapy

In the previous decade major advances were made in targeted therapies as exemplified by the great progress in lung cancer. Today therapeutic innovation is dominated by the overwhelming breakthroughs in immunotherapy.¹ This is particularly great news as these novel immunotherapeutic drugs work best in those cancers in which our targeted therapies fail: cancers with many mutations. There is a strong emerging interaction between targeted therapies and immunotherapy and it appears that targeted therapies silence oncogenic pathways that promote immune tolerance. For example BRAF inhibition with vemurafenib leads to expansion of T-cells infiltrating melanoma, a prerequisite for response to PD1/PD-L1 immune checkpoint inhibitors.

(BELG J MED ONCOL 2015;9:154–7)

Therapy-orienting testing of BRCA1 and BRCA2 germline mutations in women with ovarian cancer

With the aim to optimally position poly-(adenosine diphosphate-ribose) polymerase inhibitors in the treatment of ovarian cancer, a panel of Belgian Experts came to a national multidisciplinary consensus: (i) germline BRCA1/2 testing should be indicated for all women with high-grade serous epithelial ovarian cancer, who are in good general condition (i.e. eligible for systemic treatment with low toxicity); BRCA1/2 mutation detection ratios being about 15–20% in this group; (ii) as the finding of a BRCA1/2 germline mutation has therapeutic implications in ovarian cancer patients, the request for therapy-orienting testing should be made as soon as possible during the course of first-line treatment. Pre-test genetic counselling is important because positive testing has implications for both the patients and their relatives, and the nature of the discussions depends on whether they take place in a therapeutic or familial context. The organisation of consultations should be coordinated in a collaborative effort between clinical geneticists, and gynaecological and medical oncologists, keeping in mind that ‘fast-track’ pre-test genetic counselling and short turnaround times are required for patients for whom the test results will have a therapeutic impact. Offering germline BRCA1/2 testing to all patients with high-grade serous epithelial ovarian cancer who are eligible for systemic treatment with low toxicity will lead to a limited increase in the number of patients eligible for this test in Belgium.

(BELG J MED ONCOL 2015;9(2):65–70)

Mixed adenoneuroendocrine carcinoma (MANEC) of the colon: molecular pathogenesis and treatment

We present the case of a 30-year-old male patient with a high grade neuroendocrine carcinoma and an adenocarcinoma developed in a tubulovillous adenoma of the colon, with diffuse liver metastasis. He underwent a right hemicolectomy and received four courses of postoperative chemotherapy with cisplatin and etoposide, followed by high dose chemotherapy with autologous stem cell support. After this treatment there was a complete biochemical and radiological remission. Now, 48 months after diagnosis the patient is alive and in unmaintained complete remission. The occurrence of a high grade neuroendocrine carcinoma in a low grade colon adenocarcinoma without any intermediate phenotypes was intriguing. Comparative exome sequencing of DNA from the malignant components revealed six somatic changes in cancer consensus genes. In both tumours, we detected mutations in APC and KRAS, as well as in BCL9 and FOXP1. Only in the neuroendocrine carcinoma component did we find a mutation in SMARCA4. All mutations were absent in germ-line DNA. The finding of several identical somatic mutations in both components in the subsequent exome sequencing supports a clonal relationship between the neuroendocrine carcinoma and the synchronous adenocarcinoma. We suggest that a mutation in SMARCA4A may be responsible for the abrupt transition to the aggressive neuroendocrine phenotype.

(BELG J MED ONCOL 2015;9(1):31–34)

Developmental therapeutics at ESMO 2014

(BELG J MED ONCOL 2014;8(4):177–9)

The 35^th San Antonio Breast Cancer Symposium

Summary

From December 4^th-8^th 2012, San Antonio, Texas, was again transformed into the world’s capital in the fight against breast cancer. The 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) was a joint presentation of the Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and the Baylor College of Medicine. This years’ meeting drew nearly 8,000 participants from over 90 countries and again proved to be the number one breast cancer meeting in the world. This report does not aim to summarise the entire meeting but discusses the key highlights of the meeting.

(BELG J MED ONCOL 2013;7:31–33)

Stratified Medicine: a call for action

(BELG J MED ONCOL 2013;7:15–19)