10 Newly-Defined Molecular Types of Breast Cancer in Nature, and a Dream

Breast cancer is not one disease. We’ve understood this for decades. Still, and with few exceptions, knowledge of BC genetics – information on tumor-driving DNA mutations within the malignant cells – has been lacking. Most patients today get essentially primitive treatments like surgical hacking, or carving, traditional chemotherapy and radiation. Some doctors consider hormone therapy as targeted, and thereby modern and less toxic. I don’t.

Until there’s a way to prevent BC, we need better ways to treat it. Which is why, upon reading the new paper in Nature on genetic patterns in breast cancer, I stayed up late, genuinely excited. As in thrilled, optimistic..The research defined 10 molecular BC subgroups. The distinct mutations and gene expression patterns confirm and suggest new targets for future, better therapy.

The work is an exquisite application of science in medicine. Nature lists 31 individuals and one multinational research group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), as authors. The two correspondents, Drs. Carlos Caldas and Samuel Aparicio, are based at the University of Cambridge, in England, and the University of British Columbia in Vancouver, Canada. Given the vastness of the supporting data, such a roster seems appropriate, needed. The paper, strangely and for all its worth, didn’t get much press –

Just to keep this in perspective – we’re talking about human breast cancer. No mice.

The researchers examined nearly 2000 BC specimens for genetic aberrations, in 2 parts. First, they looked at inherited and acquired mutations in DNA extracted from tumors and, when available, from nearby, normal cells, in 997 cancer specimens – the “discovery set.” They checked to see how the genetic changes (SNPs, CNAs and/or CNVs) correlated with gene expression “landscapes” by probing for nearly 29,000 RNAs. They found that both inherited and acquired mutations can influence BC gene expression. Some effects of “driver” mutations take place on distant chromosomal elements, in what’s called a trans effect; others happen nearby (cis).

Next, they honed in on 45 regions of DNA associated with outlying gene expression. This led the investigators to discover putative cancer-causing mutations (accessible in supplementary Tables 22-24, available here). The list includes genes that someone like me, who’s been out of the research field for 10 years, might recall – PTEN, MYC, CDK3 and -4, and others. They discovered that 3 genes, PPP2R2A, MTAP and MAP2K4 are deleted in some BC cases and may be causative. In particular, they suggest that loss of PPP2R2A may contribute to luminal B breast cancer pathology. They find deletion of MAP2K4 in ER positive tumors, indicative of a possible tumor suppressor function for this gene in BC.

Curtis, et al. in "Nature": April 2012

The investigators looked for genetic “hotspots.” They show these in Manhattan plots, among other cool graphs and hard figures, on abnormal gene copy numbers (CNAs) linked to big changes in gene expression. Of interest to tumor immunologists (and everyone else, surely!), they located two regions in the T-cell receptor genes that might relate to immune responses in BC. They delineated a part of chromosome 5, where deletions in basal-like tumors marked for changes in cell cycle, DNA repair and cell death-related genes. And more –

Cluster Analysis (abstracted), Wikipedia

Heading toward the clinic, almost there…

They performed integrative cluster analyses and defined 10 distinct molecular BC subtypes. The new categories of the disease, memorably labeled “IntClust 1-10,” cross older pathology classifications (open-access: Supplementary Figure 31) and, it turns out, offer prognostic information based on long-term Kaplan-Meier analyses (Figure 5A in the paper: Supplementary Fig 34 and 35). Of note, here, and a bit scary for readers like me, is identification of an ER-positive group, “IntClust 2” with 11q13/14 mutations. This BC genotype appears to carry a much lesser prognosis than most ER-positive cases.

Finally, in what’s tantamount to a 2nd report, the researchers probed a “validation set” of 995 additional BC specimens. In a partially-shortened method, they checked to see if the same 10 molecular subtypes would emerge upon a clustering analysis of paired DNA mutations with expression profiles. What’s more, the prognostic (survival) information held up in the confirmatory evaluation. Based on the mutations and gene expression patterns in each subgroup, there are implications for therapy. Wow!

I won’t review the features of each type here for several reasons. These are preliminary findings, in the sense that it’s a new report, albeit a model of what’s a non-incremental published set of observations and analysis; it’s early for patients – but not for investigators – to act on these findings. (Hopefully, this will not be the case in 2015, or sooner, preferably, for testing some pertinent drugs in at least a subset of the subgroups identified.) Also, some of the methods these authors used came out in the past decade, after I stopped doing research. It would be hard for most doctors to fully appreciate the nuances, strengths and weaknesses of the study.

Most readers can’t know how skeptical I was in the 1990s, when grant reviewers at the NCI seemed to believe that genetic info would be the cure-all for most and possibly all cancers. I don’t think that’s true, nor due most people involved with the Human Genome Project, anymore. The Cancer Genome Atlas and Project should help in this regard, but they’re young projects, larger in scope than this work, and don’t necessarily integrate DNA changes with gene expression as do the investigators in this report. What’s clear, now, is that some cancers do respond, dramatically, to drugs that target specific mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated now with pills, often with terrific responses.

Last night I wondered if, in a few years, some breast cancers might be treated without surgery. If we could do a biopsy, check for the molecular subtype, and give patients the right BC tablets. Maybe we’d just give just a tad of chemo, later, to “mop up” any few remaining or residual or resistant cells. The primary chemotherapy might be a cocktail of drugs, by mouth. It might be like treating hepatitis C, or tuberculosis or AIDS. (Not that any of those are so easy.) But there’d be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just 1 or 2 of these investigators’ subgroups pans out and leads to effective, Gleevec-like drugs for breast cancer, that would be a dream. This can’t happen soon enough.

With innovative trial strategies like I-SPY, it’s possible that for patients with particular molecular subgroups could be directed to trials of small drugs targeting some of the pathways implicated already. The pace of clinical trials has been impossibly slow in this disease. We (and by this I mean pharmaceutical companies, and oncologists who run clinical trials, and maybe some of the BC agencies with funds to spend) should be thinking fast, way ahead of this post –

And given that this is a blog, and not an ordinary medical publication or newspaper, I might say this: thank you, authors, for your work.

Related Posts:

Cervical Cancer Screening Update: on Pap Smears, Liquid-based Cytology and HPV

The latest issue of the Annals of Internal Medicine contains 2 noteworthy papers on cervical cancer screening. The first, a systematic review of studies commissioned by the USPSTF, looked at 3 methods for evaluating abnormalities in women over 30 years:

high-grade cervical cell dysplasia (Dr. E. Uthman, Wikimedia Commons)

1. Conventional cytology (as in a Pap smear; the cervix is scraped and cells splayed onto a microscope slide for examination);

2. Liquid-based cytology (for LBC, the NHS explains: the sample is taken as for a Pap test, but the tip of the collection spatula is inserted into fluid rather than applied to slides. The fluid is sent to the path lab for analysis);

3. Testing for high-risk HPV (human papillomavirus). Currently 3 tests have been approved by the FDA in women with atypical cervical cells or for cervical cancer risk assessment in women over the age of 30: Digene Hybrid Capture 2 (manufactured by Quiagen), Cobas 4800 HPV (Roche) and Cervista HR HPV (Hologic); another Roche Diagnostics assay, Amplicor HPV, awaits approval.

These HPV assays use distinct methods to assess DNA of various HPV strains.

There’s a lot of jargon here, and I have to admit some of this was new to me despite my nearly-due diligence as a patient at the gynecologist’s office and my familiarity as an oncologist with the staging, clinical manifestations and treatment of cervical cancer. Who knew so many decisions were made during a routine pelvic exam about which manner of screening?

The main points I took away from this paper:

1. Liquid-based cytology is similar to conventional Pap smear cytology for detecting high-grade dysplasia (abnormal cells) and cervical cancer.

2. It seems that at some medical centers, and possibly overall, there’s a lower proportion of inadequate cell specimens when practitioners skip the slides and use the liquid method. This means that fewer women need be called back for another procedure.

3. Finding HPV sequences in the cervix yields many false positives, in terms of malignancy.

The researchers conclude that further studies are needed to sort out how HPV testing can improve or supplement cervical cancer screening. The main limitation is that many young women are infected with potentially cancer-causing strains of HPV, but most don’t get cervical cancer. When cervical cancer does develop that’s usually later on, a decade or longer after the relevant viral infection.

The second Annals article, a helpful narrative review, considers the practical implications of the above findings. The authors state that over 40 types of HPV can infect the cervix. They review that progression to cancer occurs along these 4 steps: HPV transmission, acute infection, persistent infection causing precancerous changes and eventually, in a subset of those infected, invasive cervical cancer.

Figure 1 is remarkably clear:

Prevalence of high-risk HPV and incident cases of cervical cancer in the U.S., 2003–2005. Surveillance Epidemiology and End Results (SEER) data for incident cases among females aged 15 to 19 years and 50 to 64 years.

The graph shows that the prevalence of HPV infection is highest among teens and women in their early 20s, and decreases in older women. By contrast, the incidence of cervical cancer rises steadily in women over 30 years and remains elevated among women in their 40s. The authors show, separately, that the rate of cervical cancer in older women is low.

The central point is that high-risk HPV infection and associated inflammation of the cervix are common in young women, but cervical cancer is rare among those under 30 years. The investigators conclude that cervical cancer screening in women younger than 20 years may be harmful. They also state that evidence supports discontinuation of cervical cancer screening in most women who are over 65 years old.

Two asides on this otherwise non-bloggy topic –

It’s great that the Annals provides the full text of these papers open-access, free of charge to the public.

Amazing how well-accepted is the concept of some viruses causing cancer, today. This was a heretical idea 25 years ago in academic medicine; now it’s dogma.

Related Posts:

What Is a Cancer Metastasis?

A metastasis refers to a lump of cancer cells that’s physically separated from the original tumor. A metastasis can be local, like when colon cancer spreads to a nearby lymph node in the gut, or distant, as when lung cancer cells generate tumors in the adrenal gland, liver, bone or brain.

Sometimes metastases cause serious damage in the organs where they’ve settled. For instance, brain “mets” can result in impaired thinking, personality changes, blindness or seizures. Liver metastases, if large enough, can result in hepatic (liver) failure. Bone mets can lead to anemia and other blood cell deficiencies if the marrow becomes filled with malignant cells instead of normal ones.

A common source of confusion is that when cancer moves from one body part to another, it’s still referred to by its site of origin.  For example, if breast cancer spreads to the liver or bone, it is still called breast cancer and most often treated as such. In general it’s the type of malignant cell, rather than the affected organ, that guides therapy.

Notes on usage: The plural is “metastases.” When someone has metastatic disease, that means their cancer has spread from the primary site to another. Oncologists don’t usually apply these terms to leukemia or lymphoma.

Related Posts:

More on DCIS

More, a magazine “for women of style & substance,” has an unusually thorough, now-available article by Nancy F. Smith in its September issue on A Breast Cancer You May Not Need to Treat.

Ductal Carcinoma in Situ (DCIS) in the breast, histopathology w/ hematoxylin & eosin stain, Wiki-Commons image

The article’s subject is DCIS (Ductal Carcinoma in Situ). This non-invasive, “Stage O” malignancy of the breast has shot up in reported incidence over the past two decades. It’s one of the so-called slow-growing tumors detected by mammography; a woman can have DCIS without a mass or invasive breast cancer.

While some people with this diagnosis choose to have surgery, radiation or hormonal treatments, others opt for a watchful waiting strategy. The article quotes several physicians, including oncologists, who consider the surveillance approach favorably and otherwise.

In 2009 the NCI sponsored a conference on diagnosis and management of DCIS. The participants issued a helpful, albeit technical, consensus statement.

The bottom line is that optimal treatment for DCIS remains uncertain because doctors don’t yet know the natural course of this early-stage breast malignancy. The ClinicalTrials.gov website lists active and ongoing studies.


Related Posts:

Two Faces of Pancreatic Cancer

Early this week I was saddened to hear of a former colleague’s death from pancreatic cancer. Dr. Ralph Steinman, a physician-researcher at the Rockefeller University, received a Nobel Prize for his work on the innate immune system. For many, news of Ralph’s death at 68 years arrived synchronously with word of his award.

Yesterday we learned that Steve Jobs, Apple creator and leader, died at 56 years from a neuroendocrine tumor of the pancreas. The tech-based, Twitter-type tributes reveal the breadth of this man’s influence on our world.

These two men faced completely different forms of cancer in the pancreas. This news underscores the importance of pathology in cancer diagnosis and treatment. For a patient to make an informed treatment decision, which might be to decline treatment, a patient needs to know what kind of cancer they have, what is the prognosis, and how might therapy change the course of the particular illness.

Jobs had a neu­roen­docrine tumor. According to the NCI, islet cell tumors of the pan­creas are quite rare, with esti­mates of between 200 and 1000 new cases per year. These can be dis­tin­guished from other cancers by special stains and mol­e­cular tests. Just months ago, the FDA approved two new drugs for treatment of neuroendocrine tumors of the pancreas: Afinitor (Everolimus) and Sutent (Sunitinib).

This kind of cancer can arise in almost any body part, but it’s most commonly found in endocrine (hormone-secreting) organs. In the pancreas, it can develop from islet cells that manufacture hormones such as insulin. Symptoms may occur if the tumors secrete active hormones, with effects elsewhere in the body, or if they cause pain by expanding and pressing on nearby nerves, vessels or ducts. These tumors tend to grow slowly and the prognosis is relatively good; doctors may advise some patients to hold off on treatment until symptoms occur.

The usual form of pancreatic cancer is of the exocrine cells, those that produce and secrete digestive enzymes into the bile duct and small intestine. According to the American Cancer Society, there are over 44,000 new cases of pan­creatic cancer yearly in the U.S. It tends to occur in the elderly and is slightly more common in men. Cig­a­rette smoking is one of the few certain dis­posing factors; the causes are largely unknown. The prognosis for this kind of pancreatic disease remains poor, on average. Standard treatments, according to the NCI, include surgery, radiation, chemotherapy and palliative care.

Related Posts:

newsletter software
Get Adobe Flash player