The Use of Targeted Therapies for Precision Medicine in Oncology

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle to develop an individualized treatment plan. It was brought to the forefront recently as President Barack Obama launched the Precision Medicine Initiative, which aims to revolutionize medicine and move the concept of precision medicine into everyday clinical practice with near-term goals focused on cancer. Clinical applications that will benefit from precision medicine include improving patient diagnosis and prognosis, predicting treatment response, and determining predisposition to certain cancers. This information will be incorporated into an individualized patient treatment plan that will provide maximum benefit while reducing the use of drugs that have serious side effects and are unlikely to benefit the patient. In addition to improving patient survival and quality of life, there will be an overall reduction in cost for the healthcare system. Targeted therapy provides the foundation of precision medicine. Even in individuals with similar clinical cancer phenotypes, drug therapy is only effective in a subset of patients. Owing to recent advances in molecular biology, genomics, and bioinformatics, research has shown that differential drug response is often a result of differences in genetic alterations. Altered genes may contribute to cancer progression by allowing growth and spread of the malignancy. Alternatively, they may contribute to drug effectiveness if there are mutations in genes involved in drug metabolism. An in-depth understanding of the biology of the tumor, including molecular changes and altered signaling pathways will allow for the identification of patients who are likely to benefit from such treatments; it also may facilitate the development of new targeted therapies, which counter the influence of the specific molecular drivers contributing to the growth and spread of the malignancy. In this Q&A article, 5 experts discuss the applications of precision medicine and how targeted therapy contributes to the overall goal of precision medicine in cancer patient management. They also address some of the challenges we face in the implementation of precision cancer therapy. The hope for precision medicine is that treatments will one day be tailored to the genetic alterations in each person's cancer. For what cancer types do you think precision medicine will have the highest impact? George M. Yousef: In order for precision medicine to have a significant impact on patient outcome, there should be a focus on: (a) cancers with high prevalence that represent an economic burden; and (b) cancers with known “trunk” mutations [according to the trunk-branch model of tumor heterogeneity] that can be targeted for therapy. Colorectal and cervical cancers are good examples. Moreover, genomic medicine will be able to subclassify cancers into specific biological subgroups with unique pathogenesis. Each subset will be a candidate for specific therapy that targets its specific pathogenic pathways. Lung cancer represents a good model in this regard, as distinct biological subtypes continue to be identified for treatment purposes. Gregory J. Tsongalis: President Obama's declaration of new initiatives in precision medicine, including the Moonshot Program to Cure Cancer, underscores the significant impact cancer continues to have on healthcare systems and wellness around the world. Precision medicine has acquired numerous meanings over the years and if we expand it to include not just therapies targeted to tumors with specific genetic variants but also to tumors that express specific mutant proteins or exhibit abnormal pathways, then we begin to impact all tumors. Early targeted therapies for cancer included assessment of the estrogen receptor in breast cancer. Today's targeted therapies include specific monoclonal antibodies such as trastuzumab for breast cancer and panitumumab for colon cancer, small molecule tyrosine kinase inhibitors such as imatinib for chronic myeloid leukemia (CML)9 and erlotinib for lung adenocarcinoma, and immunotherapies such as pembrolizumab as a PD-1 (programmed death-1) inhibitor in metastatic melanoma. The first solid tumor type for proof of principle of precision medicine was breast cancer for the therapies mentioned above. More recently, lung adenocarcinoma, colon cancer, and melanoma have been considerably impacted by precision medicine efforts. As precision medicine concepts become refined and therapeutic efficacy better understood, cancer patients will benefit from the use of new therapies as indicated by the Food and Drug Administration (FDA) and through clinical trials and off-label use of these same therapies. For example, we are beginning to see treatment strategies that include the use of an FDA-approved drug for one tumor type with a particular genetic variant in a different tumor type having the same variant. In this respect, no human cancer should go unaffected by novel treatment approaches. Louis Vermeulen: Precision medicine will be most effective in malignancies that are characterized by only a few strong driver mutations or genomic translocation events. These types of malignancies could be considered “honest” cancers. It will be much more challenging to develop effective targeted interventions for more complicated diseases with many drivers, and a relatively long and slow process of oncogenesis in which genetic aberrations accumulate and cells display complicated epigenetic rewiring. Examples of such “complex” malignancies are advanced breast cancer and lifestyle-associated colorectal and lung cancers. Indeed, the most effective targeted interventions today corroborate this notion. Imatinib displays extreme efficacy in both CML, by targeting the single required and sufficient driving kinase ABL, and in CD11710 [synonym for KIT (KIT proto-oncogene receptor tyrosine kinase)] mutant gastrointestinal stromal tumors, by inhibition of crucial c-kit kinase activity. Furthermore, targeted therapies are very effective in nonsmoking associated lung cancers displaying EGFR (epidermal growth factor receptor) mutations or ALK (anaplastic lymphoma receptor tyrosine kinase) rearrangements, but much less so in their smoking associated counterparts. Encouragingly, an increasing number of driver events are identified that often occur in very rare subsets of cancers. Examples of these include HER2 [synonym for EBBR2 (erb-b2 receptor tyrosine kinase 2)] amplification in gastric cancers that can be targeted with trastuzumab, and the recently described RSPO (R-spondin) fusion events that occur in a small percentage of colon cancers and can be targeted by anti–R-spondin antibodies. Ziqiang Zhu: Lung cancer is the leading cause of death among all cancer patients. Great efforts have been focused on both basic and clinical research of lung cancer, especially NSCLC (non–small-cell lung cancer). This work has been leading the way in the advances of precision medicine. A majority of the mutations discovered in lung cancer are actionable with either an approved drug or a drug in clinical trials. So far, more new drugs have been approved for lung cancer treatment in the past few years than in the past half century. Therefore, precision cancer therapy has already transformed the management of lung cancer. Furthermore, I believe that in the near future, the question is not where the disease originates from, but rather, which specific cancer-driving mutation(s) it harbors—and information like this will drive precision medicine. Therefore, with the advances in genetic sequencing, detecting the genetic mutations that drive tumor growth and further targeting them will transform the management of the majority of the cancer types and eventually lead to a cure. Suzanne Kamel-Reid: There are several different scenarios in which precision medicine will have the highest impact, depending on the context/definition of the term “precision medicine.” When we consider precision medicine as “the right drug for the right person at the right dose,” we can apply precision medicine through targeted therapies. The benefit of this approach has already been realized in cancers with targetable variants/mutations, e.g., BRAF (B-Raf proto-oncogene, serine/threonine kinase) in melanoma; EGFR in lung cancer. However, when we consider precision medicine through prediction of response to established therapies, we are able to use molecular information to exclude or include a patient from treatment with conventional therapies [e.g., KRAS (KRAS proto-oncogene, GTPase) mutation in colorectal cancer; CEBPA (CCAAT/enhancer binding protein alpha) double mutant in allogenic stem cell transplantation; genetic causes of drug resistance). We can also apply precision medicine as an approach to enable the use of information derived from profiling a disease to patient in a more refined This to diagnosis the of molecular or to the of patient the of Precision medicine on the of and is in it changes over It is to the and of and the for of understanding on advances in molecular profiling and as as growth in of the cancer is a patients may have tumors that the molecular of the tumor may be could tumor impact the effectiveness of targeted George M. Yousef: the effectiveness of targeted therapies, as by the tumor can also have a serious impact on the of the by molecular and patient are This is in tumors. to these include tumor on pathways than individual and for tumor that are to provide a more of the Gregory J. Tsongalis: understanding of cancer as a disease to be a certain cancer a but not to the that we all tumor can occur at and molecular tumors are of different cell types and this can impact the of mutation The molecular of these tumor cells has and will continue to impact therapeutic to mutations in novel clinical management the cell that should be characterized by different mutations may not all to the same Furthermore, some mutations may of disease to The clinical that this is not In the a similar with the and The of the to or the of with different the disease to with one drug at a to we approach cancer with that will pathways This approach will better of tumor cells that have numerous variants and be less likely to result in or metastatic disease with The of this is the most likely that new trials for novel therapies are not the significant that we for clinical trials are and of clinical trials into account the variant of tumor cells and not focus on only variant. this trials that include tumors of many different types with a therapeutic or trials where a specific tumor type is with different therapies on the molecular are the and could better treatment In trials may better facilitate the of therapies. These types of clinical the of cancer as a disease and of treatment Louis Vermeulen: of tumor is in understanding the of targeted The genetic of cancers to a the efficacy of these In of targeted drugs are in where the is For example, in lung cancers EGFR inhibitors are in tumors in which this is and a driver the of cancers are to of targeted mutations to targeted have been For antibodies are in colon cancers an mutation in the that is of patients with such mutations are from these there is In the few it has become that the in which mutations for the or the cancer are of as It has been established that driver events in different malignancies to A of this concept is BRAF mutations and BRAF The BRAF mutation in of and these tumors display response to BRAF However, in colon cancers that with the same these are the same driver but a different in drug It has been established that colon cells have different of and that in this BRAF inhibition in a of EGFR and the of BRAF This not in Ziqiang Zhu: as as This significant challenges in effective treatment cells different therapy novel drugs that of driver signaling pathways should be tailored to the genetic However, it is to which one is the cancer-driving In many if a cancer-driving mutation is the patient may not be able to benefit if there is no targeted drug therapy. In tumor may cause treatment to drug genomic are a of information to understanding of cancer diagnosis and Suzanne Kamel-Reid: may impact the effectiveness of targeted therapy in at the may not be in all cells of the tumor, and therapy may not work for a significant of cells the cancer. specific molecular such as EGFR in lung adenocarcinoma, which is associated with acquired to tyrosine kinase inhibitor targeted therapy the cancer stem cell may not the targetable variant or may be to conventional treatment to including or cancer therapies are often in by the development of drug to targeted therapies can from growth of the of the tumor that mutations and have a survival you think some cancers are more to drug than are there specific that contribute to this survival do you precision medicine can the of tumor drug George M. Yousef: Drug is a for the majority of metastatic cancer There are several and that can contribute to drug Precision medicine can provide to or the of drug through therapy and therapy that is on targeted for the pathways of and the genomic of the tumor with different of therapies, we can develop therapeutic to drug genomic of tumors can to types of targeted therapy on the genomic of the Gregory J. Tsongalis: of the of human cancer is the and survival of the cancer cells that are to a drug will new variants that result in the cell to treatment as of this survival while cells are as a that in the for an to the of may in certain tumor types I believe this is a that we will face with all tumor types to the biology of these As of we may not have to these this is in patients with metastatic disease where some are in and in in response to the same therapy. We to do a better at and these in the tumor with first therapy. As one to will be the use of therapies and development of therapies that more than one such as a tyrosine kinase The use of targeted therapies in with is over therapy to this is the use of a of therapies, including targeted small molecule and The hope is that the in management strategies by these will result in cancer a chronic Louis Vermeulen: is a for to targeted therapies. Indeed, in some with a that causes a these often with similar mutations as to in the patient as a For mutant colon cancers do not benefit from therapies, and cancers therapies display with mutant In this the of both from an as as are often cancers that with a high of are at of therapeutic on or cancer cells or can the of very small with In the future, the of these may the use of therapies that also the single drug Alternatively, drug could be that to tumor and of of a drug when a with the of more disease therapies, in their are very to Ziqiang Zhu: research has that genetic contributes to treatment to mutations to targeted tumor profiling for a better understanding of how tumors develop is for cancer Early of drug more use of targeted cancer therapy. It also to drugs that will no benefit and side the to targeted drugs could be acquired from tumor cells their to For example, the BRAF mutation is in of melanoma patients. BRAF inhibitor often to of drug a result of the of of the protein kinase) which is for tumor cell This to the development of therapy with BRAF inhibitor and protein kinase kinase) inhibitor by targeting the different in the same signaling This therapy has to be effective for the of drug in advanced melanoma. Suzanne Kamel-Reid: It is likely that some cancers are more to drug than depending on and of the tumor, in addition to the impact of the on with a mutation or genetic for example, may be to may be more likely in some cancer types than to the response to the by the therapy. cancer stem which have different than the of the tumor, may in a altered way to to a new tumor Precision medicine can be to provide a of the genetic and on the tumor and However, this that tumors be in a and through of can also be as a of patient response or [e.g., mutation number in the of for melanoma; mutations in the of myeloid In this precision medicine can be to of tumor their and treatment but not of tumor drug A clinical in cancer research is cancer can precision medicine in cancer George M. Yousef: Precision medicine can an in cancer prediction through for cancer This will enable and to be for better patient We should very cancer to the of over diagnosis and over cancer has in a number of in colorectal and cervical its in including and breast cancers a of for similar to the should be to of cancer challenges for the use of genomic profiling for cancer are the of and the of to be should be Gregory J. Tsongalis: treatment in or patients may not be the approach for cancer prevention but better with new may Precision medicine also medicine as as individual medicine. for cancer will impact and However, with to cancer we to address lifestyle and in prevention is for of the or to this the for However, having a with to is that this information all of the clinical we are cancer. may or may not be as the variants we in tumor cells are and acquired at in the of the for cancer detecting variants be cell or as as concept for prevention in in a better understanding of and its as as in the understanding of the of which is a Louis Vermeulen: The first of that to that could benefit from precision medicine in a are individuals that with genetic The of these individuals is that the driver of their is In patients with the is of the single signaling as the is already In the same concept for the It is that drugs can be to the of these often that occur of the single tumor in a such and recently that inhibition in this a to of colon cancer in In in the future, each cancer will be with driver Ziqiang Zhu: Precision medicine in cancer prevention including of cancer as as very one of the most in cancer prevention is strategies for of and cancers. way is development and of novel especially in patients cancer predisposition genes such as with high have the benefit of of such In of cancer for example, recent further mutations in alpha) may efficacy in colorectal cancer Therefore, on precision medicine strategies may the of of cancer we will have the to cancer both at the individual and to further Suzanne Kamel-Reid: Precision medicine can a of in cancer prevention through of and For example, molecular profiling can be to and genetic of and predisposition through of such as in the of and cell for better and In the identification of mutations can a better understanding of the of by their type and For example, in the are with of precision medicine in clinical Targeted therapies, which are often are of with the majority of these drugs is in only or do you think we should address this George M. Yousef: It is very to the that is not to A number of have to be to address this including with a of the and of each The patient should also be of the and the side effects of the therapy and this particular in of clinical trials is In a is to develop for implementation of or of into account and in addition to quality of and the Gregory J. Tsongalis: and this is a therapies are approved for use in patients that have and of We are only to see the of these therapies at an in the of the to these therapies, either of or is a Precision medicine as its an understanding of the genomic of the tumor cells that will them to therapy. The use of or off-label drugs be approved by who may not the clinical or However, if we at the then many that this therapy is not the same we to be or at for to and for as long as I not that I can a on this and will be with the of I can that this is not an process and the to be are very This is an that but we to with and the that and healthcare such therapies. the each patient is a for and information that understanding of of the therapies to the disease and of to with As a clinical and human for less is not but we have to the and work reducing of drugs and increasing to these drugs so that we can provide the patient Louis Vermeulen: This is a In there are several in which we should will allow to the of patients for specific targeted which will the and the should be more and the of drug development and clinical It is a that development of a new drug is in the of a that to be the we are very in predicting clinical efficacy This to be such that drugs are in the development we to a model in which the associated with drug development are and healthcare Ziqiang Zhu: a only for a few or may not we have to in that these patients are with no treatment they to targeted It is that in one of the that in the way of precision medicine more is the In targeting the right mutation in the right patient should maximum with side and and a reduction of in the long We that the cost of a has already to a few In novel and have drug development to In several recent have that survival is not associated with targeted therapies. However, there to be a the in precision cancer therapy and the significant in as a Suzanne Kamel-Reid: There are several targeted therapies as of for often in of their imatinib in in BRAF melanoma; kinase in in However, targeted therapies are often in the as a result of the of the clinical trials efforts are to consider how to the of targeted therapy by for patients with variants to targeted therapies in all of these are on clinical trials The targeted therapy to be to patient as to and in that as such as trials precision medicine into the and are on the that the of a molecular drug response, of tumor such as these will to in small patient and may you like to see in the of precision medicine for George M. Yousef: I believe that we are a new of precision medicine in which will have significant impact in improving patient It is to that precision medicine is not likely to provide a and for for most A targeted which on specific where actionable are is and should be to the of to and for genomic should be As much as I medicine of medicine that is and with patient in treatment we should also patients have the to to the precision medicine in especially in the near Gregory J. Tsongalis: I think we to the types of we are There is for more and of to which variants and are most The of by around the to be in a way that can to the clinical For example, for one to tumors is and that most likely that while some variants may be tumors no tumors have the same of As we develop a better understanding of these I think we will be able to with better I a of as I think this has been way by the clinical could genes that are or in tumor cells could then be for by I very the for the for We have to have such an with a for solid tumors. I think all of this will lead to more therapies so that cancer can become a chronic Louis Vermeulen: The of precision medicine in in prevention with the development of cancer The is the development of strategies to of in the that only a few events and are to targeted In the future, for with we will to develop therapeutic applications that can be as the tumor and mutations over In this respect, it is that at the of molecular are of and and that these of the effects of drugs to be by of or to the changes in of the cancer. This has the to of and the therapy which no effective therapies are Ziqiang Zhu: I believe precision medicine is the of medicine and especially the of the few further understanding of the molecular of cancer development and the with the will provide more effective therapies with side effects than precision cancer therapy will enable to individualized and patient and quality of Precision is one type of precision medicine that aims to a of a to cancer. We have a better understanding of how to cancer. inhibitor therapies, and therapy have been to a response and cancer to therapies. However, these therapies only work in a small percentage of patients. Therefore, there is an to the response to cancer In novel to patient and treatment response of is also especially molecular targeted therapy and will the of how we approach cancer treatment to the for majority of cancer Suzanne Kamel-Reid: A of more of molecular of molecular e.g., with mutation translocation and and where and of more drugs targeting more genes and pathways altered in a better understanding of the biological differences in and of for a better understanding of of patient management more profiling I like to see more and effective medicine for all through efforts in precision medicine. chronic myeloid leukemia Food and Drug Administration for KIT (KIT proto-oncogene receptor tyrosine kinase) growth factor receptor lymphoma receptor tyrosine kinase for EBBR2 (erb-b2 receptor tyrosine kinase proto-oncogene, serine/threonine kinase KRAS proto-oncogene, binding protein signaling Suzanne of with and

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