Genomic Complexity: A Call to Action William N. Hait1* and Arnold J. Levine2 Because of their genomic simplicity relative to mature cancers, pre-malignant tissues might harbor therapeutic targets for drugs that destroy cancers before they appear.

GLASS HALF FULL? Te U.S. national initiative that led to the sequencing of the human genome produced unquestionable advances in technologies, knowledge, and translation of that knowledge into better diagnostics and treatments for patients with cancer and other diseases. Te more “targeted” analysis of specifc diseases such as cancer through Te Cancer Genome Atlas has added immeasurably to our understanding of cancer biology and to better approaches to cancer treatment. However, further genomic analysis of progressing malignancies, although valuable, may not be the next-highest priority from a therapeutic perspective. Genomic instability and its resultant complexity has led to a Gordian knot of interlacing redundancies that could take years, decades, or forever to unravel, delaying the development of transformational therapies. In fact, a recent update (1) on the Human Cancer Genome project—based on an analysis of 5,000 tumors and matched normal tissues across 21 tumor types— 1

Janssen Research and Development, Raritan, NJ 08869, USA. 2Institute for Advanced Studies, Princeton, New Jersey and The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. *Corresponding author. E-mail: [email protected]

suggests that the frst crack at sequencing the cancer genome has given us only part of the story and that to arrive at the full picture needed to rigorously direct our drug discovery eforts will require the analysis of an additional 2,000 tumors across ~50 tumor types (that is, ~100,000 more samples) (1). Furthermore, these estimates do not include an analysis of metastatic cancers with varying propensities for diferent anatomic locations, nor do they address the conundrum that, within a single tumor mass, cancer cells may difer in their genomic makeups. A recent analysis of the genomic landscape by Vogelstein and colleagues (2) highlights this complexity and provides an impetus for alternative approaches described herein. Te pessimist will see this increasing genomic chaos as an insurmountable problem, whereas others will see it as a compelling opportunity to advance our understanding of cancer biology that will defne actionable targets for drug discovery and

Table 1. FDA-approved drugs that target a mutant oncogene product. Target protein

Drug (trade name)


Imatinib (Gleevec) Dasatinib (Sprycel) Nilotinib (Tasigna) Ponatinib (Iclusig) Bosutinib (Bosulif )

bRaf Vemurafinib (Zelboraf ) Dabrafinib (Tafinlar)

Date of frst approval


2001 2006 2007 2012* 2012

CML; gastrointestinal stromal tumors

2011 2013

Melanoma V600E mutation V600E and V600K mutations


Crizotinib (Xalkori)




Vandetinib (Zactima) Cabozantinib (Cometriq)

2011 2012

Medullary thyroid carcinoma


Afatinib (Gilotrif )


NSCLC harboring exon 19 deletion or exon 21 (L858R) substitutions


Ruxolitinib (Jakafi)



*FDA suspended marketing and sales because of the risk of life-threatening blood clots and severe narrowing of blood vessels.

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Recent next-generation DNA sequencing studies indicate that the progression of most malignancies from pre- to post-treatment status or from the primary site to a metastatic one involves a stunning increase in genomic complexity accompanied by a variety of cell-signaling redundancies. Tis plasticity associated with cancer genomes suggests that replicating the dramatic therapeutic successes of a few targeted drugs will be far more difcult than previously anticipated. Here we argue that greater attention should be applied to the earliest manifestations of cancer—that is, pre-malignancies— to determine whether such lesions display simpler genomic aberrations that increase the likelihood of pinpointing targets for transformational therapies.

ultimately yield better therapies. We would like to believe that the latter is true, that a complete catalog of all the genomic alterations in the most common cancers will not only provide new knowledge in cancer biology, but would also be an important component of the drug discovery process. Furthermore, genomic chaos may reduce the ftness of a tumor, and so genomics-based experimentation might uncover Achilles heels of advanced malignancies, thus leading to better ways to treat cancer patients. Tere are examples in which this appears to be the case; treatment of patients whose tumors harbor driver mutations, such as catalytic-domain mutations in the EGF receptor (EGFR) (for example, L858R), lead to the production of further mutations (such as T790M) that produce a new, lessft clone. Te patient can then take a “treatment holiday” that permits reappearance of the original, drug-sensitive clone (3, 4). However, full genomic sequencing of tumor versus normal tissues from patients carried out by the U.S. National Cancer Institute, genome centers, and some large laboratories on many tumor types over the past few years has shown both the advantages and limitations of knowing the driver mutations as well as numerous secondary mutations in a tumor. To date, this approach has had notable successes, but in other instances it has been frustratingly uninformative for



WHEN TO TREAT? ASAP With rare (if any) exceptions, the earlier a cancer is diagnosed and treated, the better the outcome. For most patients, the frst treatment with a new class of drug has the highest probability of response and the longest duration of remission. Te discovery and development of the Bcr-abl kinase inhibitor imatinib [for the treatment of pa-

Table 2. FDA-approved drugs developed on the basis of molecular mechanistic data. Target protein

Drug (trade name)

Date of frst approval



Trastuzumab (Herceptin) Pertuzumab (Perjeta) Ado-trastuzumab emtansine (Gilotrif )

1998 2012 2013

Breast cancer Breast cancer Breast cancer


Rituximab (Rituxan) Ofatumumab (Arzerra) Obinutuzumab (Gazyva)

1997 2009 2013

B cell malignancies, CLL


Gefitinib (Iressa) Erlotinib (Tarceva)

2003 2004


Cetuximab (Erbitux) Panitumumab (Vectibix)


Colon cancer Colon cancer

Her2/neu, EGFR

Lapatinib (Tykerb)


Breast cancer


Vismodegib (Erivedge)


Basal cell carcinoma

Table 3. CML patient–response rates to imatinib by phase of disease. Chronic phase Interferon treatment failure (400 mg; n = 532)

Accelerated phase (n = 235) (600 mg; n = 158) (400 mg; n = 77)

Myeloid blast crisis (n = 260) (600 mg; n = 223) (400 mg; n = 37)

Percent of patients [95% CI*] Hematological response† (HR, overall)

95% [92.3-96.3]

71% [64.8-76.8]

31% [25.2-36.8]

Complete hematological response (CHR)




*CI, confidence interval. †For HR criteria, see (8).

tients with chronic myelogenous leukemia (CML)] and trastuzumab (for the treatment of patients with Her-2/neu–positive breast cancer) are landmarks in targeted therapies for cancer. But as with other therapies, the earlier patients are treated with imatinib or trastuzumab, the better the clinical results (Table 3). It seems unsound to apply selection pressure to a patient’s cancer and drive the emergence of more complex cancers with the hope that this process will uncover new and more efective treatments. Te risk-beneft calculations to date have skewed the drug-development process toward testing new drugs in advanced, previously treated cancer patients frst, before moving to treatment-naïve patients with early-stage cancers. We respectfully propose several alternative approaches. First, because the earlier a patient is diagnosed the better the result, we should be turning our most powerful scientifc minds and technologies to the earliest known manifestations of the disease:

pre-malignancies. Second, afer Phase 1 studies that determine the safety of a new drug, pharmaceutical companies should be encouraged to focus on previously untreated patients rather than routinely beginning with studies of patients with relapsed and refractory disease; the latter are the least likely to beneft and the most likely to sufer side efects of treatment. Window-ofopportunity studies, such as those carried out in the neoadjuvant setting, provide an excellent opportunity for new-drug testing in previously untreated patients. Whereas we have an abiding interest in the rare hereditary forms of cancer driven by increasingly tractable germline mutations, relatively little is known about the genomics or biology of pre-malignancies. For example, since the seminal studies of Vogelstein and colleagues (6), thousands of colonic polypectomies were performed each year, yet little is known about the factors that initiate progression from an at-risk colonic epithelium to the formation of a

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drug discovery, even when the resultant treated tumor acquires genomic instability and predictable mechanisms of resistance. Te earliest progress from sequencing advanced tumors and comparing these results with those from primary tumors gives us insights into why translating these results into new therapies has been slower than expected (5). For example, it has not yet been consistently possible to distinguish driver mutations from other mutations with unknown signifcance. Since regulatory approval of the frst Bcr-abl inhibitor (imatinib) in 2001, there have been only a few other proteins targeted with U.S. Food and Drug Administration (FDA)–approved drugs based on gene mutations, deletions, or translocations (Table 1). Other important drugs—such as those that block members of the EGFR family (Her1, Her2, Her3), surface antigens such as CD20, and components of the hedgehog pathway (SMO)—were developed on the basis of a deep understanding of the molecular and cellular biology of specifc tumor types, including lung cancer (erlotinib and geftinib), breast cancer (trastuzumab), B cell malignancies (rituximab), and basal cell carcinoma (vismodegib) (Table 2). Te percentage of driver mutations in diferent tumor types varies (2). Yet, very few drugs have been developed for the most common examples—the tumor suppressor p53 and the protooncogene products Ras and Myc. To date, even when a driver mutation is present and a drug has been approved, the overall beneft for the majority of patients is frustratingly low. For example, adenocarcinomas represent ~40 percent of lung cancers. Activating EGFR mutations and EML4:alk translocations are present in only 10% in Caucasians (higher in Asians) and 2 to 7% of adenocarcinomas of the lung, respectively. Tus, only 4% of lung cancer patients might potentially beneft from drugs that target mutant EGFR, and only 0.8% to 2.8% would beneft from an Alk inhibitor, assuming these drugs were 100% efective, which they are not.


C O M M E N TA R Y our new-found abilities to sequence B and T cell receptors from blood could become a rapid test for monoclonal gammopathies in elderly people, and these cells could be used to study disease mechanisms and progression for other monoclonal proliferative disorders derived from other precursor cells in the hematopoietic pathways. One of the most interesting new directions to come from studying pre-malignancies is the ability to test the hypothesis that the frst genetic alteration found in a pre-malignancy determines the pathway of mutations that lead to the malignancy. It is also possible that several diferent “second mutations” exist in diferent tumors that arise from a single type of pre-malignancy. From these kinds of studies, we might be able to characterize the natural histories of diferent cancers by tracking the path of genetic alterations that give rise to that cancer subtype. Tis map can be a starting point for the fashioning of new treatment regimens. Why is so little attention paid to predisease syndromes compared to established diseases? One highly respected physicianscientist stated that he is not studying premalignancies because his patients don’t die of pre-malignancies. Exactly. Tis is reminiscent of two shoe-salesmen sent of by their boss to size up the opportunity for selling their shoes in an emerging market. Te frst returned and delivered the bad news: “Tese people don’t wear shoes.” Te second returned and delivered the good news: “Tese people have no shoes.” Yet stopping the disease at this nonfatal point in the disease continuum is rarely a priority. A statistician colleague summed it up perfectly when he remarked that “…the problem with prevention is that nothing happens.” Another factor is that many or even most pre-malignancies do not progress to invasive cancers. But by conducting rigorous analyses of these precursor lesions, it should be possible to more accurately determine the bad actors. It is also possible that we have been lulled into a sense of security as a result of the success of certain screening eforts followed by surgical extirpation, such as for cervical, colorectal, and nonsmall cell lung cancers (NSCLCs). Still, even in countries where screening and surgical procedures are available, the compliance is relatively low and in the case of colorectal

cancer and NSCLC, the devastation from the disease remains high. Finally, a premalignancy research efort will necessitate a concerted approach to obtain carefully annotated biopsies of pre-malignant tissues, which will require an expansion of current eforts being conducted by most large cooperative- and industry-sponsored trials. Because every malignancy has a premalignant condition and the closer one moves to a normal but susceptible tissue the simpler the biology, we should be clamoring for more research on pre-malignancies conducted with the same skill and sense of urgency that our scientifc leaders have applied to unraveling the last bit of genomic complexity of every type of terminal cancer. REFERENCES

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Genomic complexity: a call to action.

Because of their genomic simplicity relative to mature cancers, pre-malignant tissues might harbor therapeutic targets for drugs that destroy cancers ...
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