HER2 Abnormalities Found In Many Advanced Cancers

Date: Jun-03-2013We already know that an over-active HER2 growth factor gene features in breast and gastric cancers. Now a new study
reports finding mutations and other abnormalities of the gene in 14 different advanced cancers.

Massimo Cristofanilli, Director of the Jefferson Breast Center at the Kimmel Cancer Center and Thomas Jefferson University
Hospital, announced the study results at an oral presentation during the annual meeting of the American Society of Clinical
Oncology (ASCO), which is taking place in Chicago until Tuesday.

The gene for human epidermal growth factor receptor 2 (HER2) codes for a protein that promotes the growth of cancer cells. In
around 1 in 5 breast cancers, a mutation in the gene causes cancer cells to make too much HER2 protein. The same mutation
and the higher protein levels that result, occur in many types of cancer.

But Cristofanilli's results suggest there may be several kinds of gene alteration that can have this effect: not just known
mutations but also other irregularities such as amplifications, substitutions, and translocations.
Cancer As a Disease of Gene Alteration
Cancer is essentially a disease of failure to regulate tissue growth. It is when the genes that regulate normal cell growth become
altered in some way that the cell becomes cancerous.

Every time a cell divides, the enormous amount of data contained in its genetic material is replicated. When this happens, the
chances are that some errors (mutations) will occur. Cells have complex mechanisms to prevent and correct such errors. And
even if the faulty cell survives, there is another process, cell suicide or apoptosis, that the body uses to deal with rogue
cells.

But if all these error controls fail, then the mutations and alterations survive and are passed on to daughter cells, to sow the seeds
of a tumor.

Large-scale mutations occur when a large portion of genetic material is deleted or an extra portion is added. Amplification is when
a cell gains many copies of genetic material, usually containing genes known to be cancer-causing. Translocation is when two
separate regions become fused.

Small-scale mutations such as point substitutions, deletions and insertions are alterations to the building block units of DNA. For
instance, a substitution is a mutation that exchanges two letters of the DNA code, like changing the spelling of a word by
swapping around two of its letters.

Small-scale mutations usually affect the expression of a gene and alter the function or stability of the protein it codes for.

There are also other ways genes can change to make cells cancerous, such as when viruses insert bits of their DNA into the
genetic material of the host cell, causing, for example, switched off cancer genes to switch on.
HER2 Irregularities Found In 14 Different Cancers
In this new study, which examined more than 2,000 tumors, Cristofanilli, a professor of Medical Oncology, and colleagues, found
HER2 gene irregularities in 14 different advanced solid tumors.

"No one ever thought that there would be such a variety of genomic alterations in HER2 in this many solid tumors," Cristofanilli
says in a statement.

But he says the findings could be good news, "both clinically and scientifically".

It could mean Herceptin and other anti-HER2 cancer therapies that are already in clinical use might help patients with some of
these tumors.

From a research point of view, the results add weight to the growing idea of "genome-driven therapy", where the genome
profile of the tumor, rather than where it develops, is more important when considering how best to treat the individual patient's
cancer.

A number of institutions donated tumor samples for analysis, and their researchers are co-authors of the study.  Cristofanilli
contributed about 50 breast cancer samples. He discovered that one sample showed one of his patients, who had been diagnosed
with triple negative breast cancer, had an HER2 mutation.

"My patient was treated with Herceptin as well as chemotherapy, and derived clinical benefit," says Cristofanilli.

"No one looks for HER2 mutations in this form of breast cancer. To me, this makes the case for the value of genome-driven
therapy," he explains.
Study Screened for 182 Gene Alterations Known to Be Linked to Cancer
Foundation Medicine, a cancer diagnostics company in Cambridge, Massachusetts led and paid for the study. They screened
2,223 solid tumor specimens from 20 different advanced cancers, for more than 182 genes alterations known to be linked to
cancer.

The results showed HER2 alterations in 14 types of solid tumor. Of these, 29% were esophageal cancer samples, 20% were
uterine, 14% were breast, 12% were stomach, and 6% were lung.

They also found large variations in HER2 abnormalities. They found nearly 5% of samples had 116 different abnormalities,
including 58% with amplifications, 25% with substitutions, 14% with insertions or deletions, 2% with splice site variants, 2% with
translocations, and 5% with more than one alteration. Plus, two of the tumors had both HER2 substitution and
amplification.

Cristofanilli says the study "highlights the need to study a broad range of genes at a high level of sensitivity and specificity when
searching for novel targets of therapy".

"Widespread use of this approach could provide more treatment options and enable more rapid accrual to ongoing and planned
trials of agents targeting pathways under study," he adds.

Another study reported earlier this year found that while some gene alterations may actively drive tumor growth, there may also
be some "passenger" alterations that do the opposite and slow cancer down, suggesting cancer may not be a sequence of inevitable
accumulation of driver events, but a delicate balance between drivers and passengers.

Written by Catharine Paddock PhD

View drug information on Herceptin.

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