KRAS Mutation in Oncology: Clinical Trial Insights
Intro
KRAS mutations are becoming a significant focus in the landscape of oncology, as these genetic alterations can dramatically influence treatment pathways and outcomes for cancer patients. The prominence of this mutation in various cancers, particularly pancreatic, colorectal, and lung cancers, underscores the urgent need for comprehensive exploration. Observing trends and outcomes of clinical trials involving KRAS-targeted therapies provides invaluable insights into how these mutations play a role in patient responses to treatment.
The journey of understanding KRAS mutations is not just about identifying them but also about tailoring treatments that can effectively address the unique challenges they present. The failure of many traditional therapies to produce substantial results in patients with KRAS mutations necessitates the development of targeted approaches. These efforts are often framed within the broader context of precision medicine, where treatments are customized to the individual characteristics of each patient's tumor.
As we delve into the subsequent sections, we will explore the methodologies employed in recent clinical trials, discuss interpretations of results obtained, and highlight practical avenues for future research. Across these discussions, the central aim remains to clarify the evolving landscape of oncology through the lens of KRAS mutations.
Preface to KRAS Mutations
KRAS mutations have become a cornerstone in the study of cancer biology and therapeutic strategies. Understanding KRAS is crucial since it plays a pivotal role in many cancers, especially pancreatic and colorectal cancers. This section aims to shed light on the significance of KRAS mutations, detailing their definition, characteristics, and prevalence.
Definition and Characteristics of KRAS
KRAS, or Kirsten rat sarcoma viral oncogene homolog, is a gene that encodes a protein involved in transmitting signals within cells that regulate cell growth and division. When the KRAS gene is mutated, it can lead to uncontrolled cellular proliferation, a hallmark of cancer. To paint a clearer picture, it’s useful to think of KRAS as a switch. Under normal circumstances, this switch toggles on to promote cell division. However, mutations can cause it to jam in the “on” position, sparking a cascade of cellular events that can rapidly escalate into tumor formation.
One key characteristic of KRAS is its ability to exist in multiple forms, each influenced by specific mutations. The three most common mutation types involve codons 12, 13, and 61. Each mutation type exhibits different behaviors and associated cancer types, making the landscape of KRAS quite complex. This complexity, however, is what makes the exploration of KRAS mutations particularly compelling in clinical settings.
Prevalence and Types of KRAS Mutations
KRAS mutations are not rare outliers; in fact, they are among the most frequently occurring mutations in human cancers. Approximately 30% of all human tumors harbor a KRAS mutation. In pancreatic cancer, the figure jumps to over 90%, while in colorectal cancers, around 40% of cases exhibit these mutations. Such prevalence underscores the pressing need for targeted research and therapeutic strategies.
The type of mutation can also influence cancer behaviour and response to treatments. Mutations at codon 12, often denoted by glycine to valine (G12V) or glycine to aspartic acid (G12D), are particularly prevalent and are linked to aggressive disease forms. In contrast, mutations at codon 13 are less common but may present distinct clinical challenges. With this knowledge, researchers and clinicians alike are beginning to understand that not all KRAS mutations are created equal.
"As we delve deeper into the world of KRAS mutations, identifying specific types can be as essential as the treatment itself, impacting both prognosis and therapeutic decisions."
Clinical Implications of KRAS Mutations
When delving into the world of cancer biology, KRAS mutations emerge as pivotal players. They contribute significantly to various forms of malignancies, primarily pancreatic, colorectal, and lung cancers. Understanding the implications of these mutations is crucial as they not only illuminate the mechanisms driving cancer but also offer insights into patient management and treatment strategies.
In the clinical landscape, the presence of a KRAS mutation poses unique challenges but also presents distinct opportunities. This section explores how KRAS mutations impact cancer pathogenesis and patient outcomes, thereby shaping modern oncological practices.
Impact on Cancer Pathogenesis
KRAS mutations act as the gatekeepers in cellular signaling pathways, primarily the RAS-RAF-MEK-ERK pathway, which controls cell growth and differentiation. When these genes mutate, they can disrupt normal cellular processes, leading to uncontrolled proliferation. This disruption is akin to a car engine running on a faulty spark plug: it may start, but it sputters and ultimately leads to breakdown. The mutant KRAS protein continuously signals cells to grow and divide, bypassing the regulatory checkpoints that would normally halt cell division.
The mutational landscape of KRAS is complex, exhibiting various mutation types, including the well-known G12C, G12D, and G13D. Each variant carries its own unique signature and is associated with specific cancer types and behaviors. For instance:
- G12C is predominantly found in lung adenocarcinomas, with particular sensitivity to emerging targeted therapies.
- G12D mutations are common in pancreatic cancer and correlate with poorer survival rates.
As a result, the presence of particular KRAS mutations provides insight into not just cancer biology but also the expected clinical behavior of the tumor. This knowledge allows oncologists to tailor treatment approaches based on the specific KRAS mutation profile, ideally improving therapeutic efficacy.
"Understanding KRAS mutations is not merely academic; it shapes the very strategy with which we tackle cancer treatment."
Correlation with Patient Outcomes
The correlation between KRAS mutations and patient outcomes is a rapidly evolving area. Studies have shown that patients with specific KRAS mutations often have distinct prognoses. For example, those with G12C mutations tend to respond better to targeted inhibitors than patients harboring G12D mutations. This distinction underscores the importance of precise genetic profiling in treatment planning.
Such correlation with outcomes has led to the emergence of personalized medicine, where treatment plans are tailored based on the genetic makeup of an individual’s cancer. Here are key considerations regarding patient outcomes related to KRAS mutations:
- Response to Treatment: Clinical trials show varied responses to standard chemotherapy in KRAS-mutated cancers. While some patients may experience favorable outcomes, many do not, emphasizing the need to consider KRAS status in treatment decisions.
- Survival Rates: The persistence of KRAS mutations, especially in advanced disease stages, has been associated with decreased overall survival. Ongoing monitoring of KRAS status can provide oncologists with important information to adjust treatment plans proactively.
- Recurrence Risk: Understanding the KRAS mutation can also aid in predicting the likelihood of cancer recurrence, thus guiding follow-up monitoring and interventions.
Ultimately, the clinical implications of KRAS mutations extend beyond mere diagnostics; they lay the groundwork for informed treatment choices that could lead to better patient outcomes. As research continues to unfold, the landscape surrounding KRAS mutations promises to become even more nuanced, especially concerning personalized medicine approaches.
Overview of KRAS-targeted Therapies
The exploration of KRAS-targeted therapies is essential in understanding how to combat cancers driven by this particular mutation. KRAS mutations often present considerable challenges in treatment strategies due to their underlying complexities. As researchers dive deeper into this terrain, the focus on developing effective therapeutic approaches becomes increasingly relevant. This section bridges the gap between basic mutation science and practical therapeutic application, setting the tone for pivotal breakthroughs in oncology.
Mechanisms of Action
The mechanisms of action for KRAS-targeted therapies are at the heart of their efficacy. At its core, KRAS operates as a vital component in the cell signaling pathways that control cellular growth and division. Therefore, targeting this mutation has significant implications for disrupting cancer cell proliferation.
Typically, the action mechanisms can be categorized as follows:
- Inhibition of KRAS Signaling Pathways: Several agents are designed to obstruct the downstream signaling cascades initiated by KRAS. For instance, the use of small molecules can block KRAS from engaging with its effectors, thus preventing the tumorigenic signals from manifesting.
- Targeting Adaptor Proteins: Some therapies focus on targeting the proteins that aid in KRAS signaling. By disrupting the interaction between KRAS and these adaptor proteins, researchers aim to hinder tumor growth.
- Downstream Pathway Inhibition: Achieving disruption in downstream pathways, such as the MAPK cascade, is another strategy. Therapies targeting the MEK or ERK proteins involved in this pathway aim to reduce the proliferative signals, potentially leading to apoptosis (programmed cell death) in KRAS-driven tumors.
The development of these mechanisms exhibits an evolution from a broad-spectrum approach to more refined strategies that focus on the specific mutations and the cellular context in which they occur.
Current Therapeutic Approaches
Currently, various therapeutic approaches have emerged, reflecting the dynamic landscape of KRAS-targeted therapies. These approaches encompass several categories:
- Monoclonal Antibodies: Agents like cetuximab have been employed in some cases to target the epidermal growth factor receptor (EGFR). However, their effectiveness can be limited based on the presence of KRAS mutations within tumors, which necessitates careful patient stratification.
- Small Molecular Inhibitors: Advances have led to the development of small molecules specifically designed to target KRAS itself. Drugs such as sotorasib showcase the potential to provide targeted inhibition of KRAS G12C mutations, illustrating a new era in targeted therapy.
- Combination Therapies: Employing a combination of treatments can yield improved outcomes. This might include pairing a KRAS inhibitor with chemotherapy or immunotherapy to leverage synergies that address both primary and resistant cancer cell populations. Combining therapies can often help overcome resistance mechanisms that single-agent treatments may face.
Understanding these therapeutic strategies not only sheds light on current treatment options but also emphasizes the significance of ongoing research. Continued innovation in the field of KRAS-targeted therapies symbolizes a beacon of hope for many patients navigating the complexities of cancer.
Key Clinical Trials Involving KRAS Mutations
The landscape of cancer treatment has transformed significantly with the identification of KRAS mutations. These trials have been pivotal in illuminating the role of KRAS in various cancers, providing both researchers and clinicians with vital insights into tailoring therapies. By focusing on crucial elements of these trials, we can see how they inform patient management decisions and guide future research direction.
Milestones in KRAS Research
KRAS mutations, particularly in cancers such as pancreatic, colorectal, and lung cancer, have been a major focus over the years. Researchers have marked several key milestones that have propelled our understanding of KRAS biology:
- Discovery of KRAS: Identified in the 1980s, the mutation was linked to several cancers. This sparked further investigation to comprehend its role in tumorigenesis.
- Identification of Specific Mutations: The realization that different KRAS mutations (like G12C, G12D) can influence tumor behavior and patient outcomes began to clarify targeted treatment possibilities.
- Validation of Targets: The development of specific inhibitors began in the late 2010s, with trials validating the effectiveness of these treatments in individuals with specific mutations.
Major studies such as the COMPASS trial and the KRYSTAL-1 study have highlighted these milestones, underscoring the increasingly sophisticated capabilities of molecular oncology to tackle KRAS-driven cancers.
The study outcomes have not only supported drug development but also emphasized the necessity of comprehensive diagnostic testing in clinical settings. As researchers equip themselves with new tools to decipher KRAS complexities, better patient stratification is likely to follow.
Pivotal Trials and Their Results
Pivotal trials make concrete contributions to understanding KRAS mutations and their implications for treatment efficacy. One significant trial was the KRASG12C inhibitor trial, which assessed the effectiveness of mobocertinib in patients with KRAS G12C mutations. Results indicated:
- Successful reduction in tumor size for some participants, implying that targeted therapy can significantly improve outcomes in KRAS-mutated tumors.
- Overall response rates showcased that tailored therapies could be more effective than standard treatments for specific mutations.
The evolution of therapeutic strategies for KRAS mutations marks a fundamental change in oncology. Trials are progressively shaping clinical practice patterns in assessing patient heterogeneity, thus enhancing treatment precision.
Other notable trials include:
- PEARL trial: Investigating the combination of panitumumab with chemotherapy, showing improved survival rates for patients with certain KRAS mutations.
- DESTINY study: Focusing on the efficacy of antibody-drug conjugates for tumors harboring KRAS mutations, highlighting the versatility of treatment approaches.
These rigorous studies highlight the need for ongoing research and emphasize the importance of understanding the underlying genetic mechanisms. Each trial serves as a stepping stone toward refining existing cancer therapies, enabling clinicians to select and personalize treatment plans better.
In summary, clinical trials involving KRAS mutations play a fundamental role in shaping our approach to oncological care. They deepen our understanding, promote innovative therapies, and ultimately pave the way for more personalized, effective treatment options.
Challenges in Targeting KRAS
Targeting KRAS mutations has become a pivotal focus in cancer research, but it is not without its hurdles. As we dive into these challenges, we unearth a complex web of biological, clinical, and therapeutic impediments that require diligent navigation.
Resistance Mechanisms
One primary challenge in effectively targeting KRAS mutations is the emergence of resistance mechanisms. Cancer cells are notorious for their adaptability. When treatment begins, some cancer cells may initially respond but then find ways to evade the strategies deployed by targeted therapies. There are several pathways through which these resistance mechanisms can manifest:
- Activation of Alternate Signaling Pathways: When KRAS is inhibited, cancer cells may activate other oncogenes or growth factor pathways to sustain their proliferative advantage. For instance, EGFR or PI3K pathways can compensate for the blocked signaling, leading to therapeutic failure.
- Mutations in Downstream Effectors: Often, mutations do not just lie within KRAS itself but extend to downstream signaling components. Changes in proteins like BRAF or MEK can drastically affect treatment responses. These mutations may render therapies ineffective and complicate the landscape for oncologists.
- Genetic Heterogeneity: Tumors are rarely a homogenous collection of cells. Instead, they can comprise a mutational mosaic with various KRAS mutations co-existing. This genetic diversity makes it difficult to predict how a tumor will respond to a single therapeutic approach, emphasizing the need for more tailored strategies.
Understanding these mechanisms is not merely academic; it shapes clinical strategies and informs the design of new drug combinations aiming to outsmart the cancer cells.
"Resistance is not just an obstacle; it’s a stark reminder that cancer’s complexity requires a multifaceted approach to therapy."
Patient Stratification and Personalization
Personalized medicine is often touted as the Holy Grail of modern oncology, especially in the context of targeting KRAS. Patient stratification involves categorizing patients based on specific characteristics of their cancer to tailor treatments effectively. Key considerations here include:
- Biomarker Identification: A significant aspect of patient stratification is the identification and utilization of specific biomarkers that can predict responses to KRAS-targeted therapies. If a patient has a particular KRAS mutation, understanding its effects on the cancer’s biology is crucial for choosing the right treatment regimen.
- Clinical Trial Inclusivity: There’s increasing emphasis on designing clinical trials that not only focus on KRAS status but also consider the overall genetic landscape of the tumors. This inclusion helps ensure that the findings are applicable across a more extensive range of patient demographics and cancer subtypes.
- Therapy Combination: Combining therapies based on individual patient profiles can enhance efficacy. Understanding how different mutations interact can lead to innovative treatment options that target multiple pathways simultaneously, aiming to overcome resistance and improve outcomes for patients.
Overall, the journey towards effective KRAS targeting is fraught with complexities that require a concerted effort from researchers and clinicians alike. Addressing these challenges through innovative strategies and patient-focused approaches remains critical to unlocking the potential of KRAS-targeted therapies.
Recent Innovations in KRAS Research
Recent advancements in the understanding of KRAS mutations have profoundly influenced therapeutic approaches in cancer treatment. As research delves deeper into the complexities of KRAS, it brings forth new possibilities in combating malignancies traditionally deemed resistant to standard treatments. Therefore, tracking these innovations isn't just about staying current; it’s crucial for optimizing patient outcomes.
Emerging Therapeutic Agents
Within the landscape of KRAS research, several emerging therapeutic agents are making waves. These agents are focused on directly inhibiting mutated KRAS or targeting downstream signaling pathways that are activated when KRAS is mutated. One notable example is adagrasib, which has shown promise in targeting the KRAS G12C mutation, one of the most common KRAS mutations found in patients. This agent has demonstrated substantial clinical response rates, changing the treatment paradigm for patients who had limited options previously.
Other agents like Sotorasib are also paving the way for targeted therapies, as they aim to bind to the mutated KRAS protein, disrupting its function. Networking these agents with existing treatments, like chemotherapy or immunotherapeutics, brings a fresh lens to treating KRAS-driven cancers.
Moreover, researchers are exploring the use of nanoparticle-based delivery mechanisms to enhance the effectiveness of these agents while reducing toxicity. This method not only improves the specificity of drug delivery but also has the potential to overcome some resistance mechanisms.
The Role of Combination Therapies
Combination therapies are gaining traction in KRAS mutation research, emphasizing a strategy that utilizes multiple treatment modalities to target various aspects of cancer biology. This approach recognizes that resistance can occur when tumors find ways to evade single-agent therapies.
Some promising combinations include:
- Targeting KRAS with immune checkpoint inhibitors: By pairing agents that inhibit KRAS mutations with immunotherapies, researchers are observing synergistic effects that bolster the immune response against tumors.
- Chemotherapy and targeted therapy: Utilizing traditional chemotherapy in conjunction with new targeted treatments can help amplify the overall effectiveness of the regimen, especially in KRAS-positive tumors.
- Integrating targeted therapies with radiation: Combining targeted agents with radiation therapy opens pathways for a comprehensive approach to tumor ablation while minimizing collateral damage to healthy tissues.
"Innovation in treating KRAS mutations is not just about finding new drugs; it’s about cleverly weaving existing therapies into a single coherent strategy that addresses the multifaceted nature of cancer."
In summary, the innovations observed in KRAS research manifest not merely as drug candidates but as elements of holistic treatment frameworks that proactively combat the challenges posed by KRAS mutations.
Integrating these approaches is essential as the medical community aims to keep pace with the rapidly evolving landscape of oncological care. Embracing a more nuanced understanding of KRAS will likely lead to improved prognosis for many patients, representing a critical step forward in oncology.
Future Directions in KRAS Mutation Studies
Current research into KRAS mutations has not only opened new avenues for targeted therapies but also set the stage for innovative approaches to understanding cancer on a molecular level. As advancements in technology and our understanding of genetics continue to evolve, the future holds promising developments in KRAS mutation studies. This section emphasizes the importance of progressive thinking in trial designs and highlights the potential for personalized medicine, which could drastically alter treatment efficacy and patient outcomes.
Innovative Trial Designs
When considering the landscape of clinical trials, it's clear that traditional methods may not be sufficient to address the complexities presented by KRAS mutations. Innovative trial designs are emerging to better accommodate the unique properties of these genetic alterations. One such approach includes adaptive trial designs, which allow researchers to modify aspects of the study based on interim results. This flexibility not only streamlines the process but also enhances the likelihood of capturing valuable data quickly.
Moreover, basket trials—studies that group together patients with various tumor types harboring similar mutations—present an exciting opportunity. These trials enable a focus on the molecular characteristics rather than the type of cancer, providing insights into how KRAS mutations across different cancers respond to specific therapies. By breaking the mold of conventional trials, researchers can efficiently evaluate treatments targeting KRAS mutations across diverse populations, increasing both study rigor and relevance.
In this ever-changing landscape, it’s crucial to incorporate real-world evidence into trial designs. Utilizing data from previous studies and current patient outcomes can enhance the validity of findings and drive personalized approaches. By incorporating these innovative trial designs, researchers are much better poised to tackle the intricacies of KRAS mutations, leading to advances that could fundamentally alter the treatment paradigm.
Potential for Personalized Medicine
Personalized medicine has gradually taken center stage in oncology, particularly concerning KRAS mutations. The intricate interplay between these mutations and patient-specific responses means that a one-size-fits-all approach is no longer viable. The potential for tailoring therapies to individual genetic profiles could result in more effective treatments with fewer side effects.
With the identification of different KRAS mutation subtypes, researchers are gearing up to create targeted therapies that are specifically attuned to these variations. For instance, not all KRAS mutations behave the same way in all patients. As understanding deepens, we can envision scenario where oncologists utilize genetic profiling to guide therapy choice, prioritizing treatments that target the specific mutation a patient possesses.
Through integrative approaches—merging genomics, proteomics, and patient health records—it is possible to paint a clearer picture of how KRAS mutations affect tumor biology. This understanding could lead to biomarkers that predict therapeutic response, advancing the field toward more successful patient outcomes.
"In the realm of personalized medicine, success hinges not only on the right treatment but on the right timing and the right patient."
Looking ahead, the potential for personalized medicine based on KRAS mutation characteristics is not just a theoretical ideal; it’s within our grasp. By fostering a deeper understanding of genetic profiles and their clinical implications, the transition towards more effective treatments and better patient prognoses is certainly on the horizon.
Ethical Considerations in KRAS Research
In the rapidly evolving field of cancer research, the implications of KRAS mutations extend beyond mere clinical efficacy. These mutations play a pivotal role in shaping treatment paradigms and thus beckon for a thorough examination of the ethical considerations surrounding their study and treatment. Addressing these issues isn’t just about compliance with regulations; rather, it influences the very fabric of research and patient interaction.
Understanding ethical considerations can surface several critical aspects:
- Informed Consent: It is paramount that patients are fully aware of the nature of the trials they are entering. This includes comprehending the potential risks, benefits, and the research's experimental nature. With KRAS mutations often linked to aggressive cancers, ensuring patients feel empowered in their decision-making processes is vital for ethical integrity within clinical trials.
- Patient Rights: Patients must be treated with dignity and respect throughout their participation. This necessitates not only conveying information but also protecting their rights during the trial. Knowledge about how their genetic data, especially concerning KRAS mutations, is used is crucial in fostering trust between researchers and participants.
These underpinnings feature a foundation that nurtures a collaborative relationship, enhancing the study’s outcome while safeguarding individual rights.
"Consent is not merely a formality; it is the pivotal factor that fortifies the bond of trust between healthcare providers and their patients."
Informed Consent and Patient Rights
Informed consent stands as a cornerstone of ethical research practices. When dealing with KRAS mutations, the stakes are particularly high due to their implications in cancer progression and treatment options. Patients often feel overwhelmed by the complexities of such trials and the scientific jargon that accompanies the information provided. Therefore, it helps if physicians utilize clear, straightforward language to elucidate the processes involved.
A thoughtful approach might include:
- Clear Explanations: Describe the purpose of the trial, its design, and how it aims to advance knowledge of KRAS functions in oncology. This helps demystify the process and elucidates the significance of KRAS in the larger context of patient care.
- Repeat and Reflect: Allow patients the opportunity to ask questions multiple times. This can reinforce understanding and ensure they feel confident in their decision.
- Diverse Languages and Formats: Materials should be accessible, accommodating patients with different language preferences or educational backgrounds. Providing information in various formats increases comprehension and empowerment across diverse patient populations.
Balancing Innovation with Patient Safety
When researchers forge ahead with new therapies targeting KRAS mutations, balancing innovation with patient safety becomes a daunting challenge. The inherent risks associated with novel treatments necessitate rigorous oversight and monitoring.
Here are some principles to navigate these ethical waters effectively:
- Rigorous Adverse Event Reporting: Monitoring participants for adverse effects ensures they remain safe throughout the trial. Ethical obligations dictate that these reports are taken seriously and acted upon swiftly, should complications arise.
- Adaptive Trial Designs: Implementing adaptive designs allows for modifications to the trial based on interim findings. This flexibility can mean stopping a trial or altering doses if safety concerns come to light, thereby prioritizing patient welfare.
- Regular Ethical Reviews: Establishing an independent board to monitor ongoing trials can enhance accountability. This group can assess not only the clinical aspects but also ethical dimensions pertinent to patient safety and rights.
Through these measures, researchers can strive to create a safe environment that respects the pioneering spirit of innovation while protecting those at the heart of this research – the patients.
End
In summary, the exploration of KRAS mutations in oncology is not just an academic pursuit; it holds substantial implications for both clinical practice and future research. The ability to pinpoint and comprehend these mutations can significantly alter treatment strategies and enhance patient outcomes.
Reevaluating the Role of KRAS in Oncology
Traditionally, KRAS mutations have been viewed as mere markers of specific cancers, especially pancreatic and colorectal types. However, recent findings suggest that these alterations are far more pivotal in cancer biology than previously thought. Researchers have begun to connect the dots, realizing that KRAS doesn’t just enable tumors to grow, it shapes the tumor microenvironment and dictates how cancer cells interact with therapies. This reevaluation encourages oncologists to factor KRAS status into their treatment decisions more strategically.
Moreover, emerging data highlight the idea that KRAS mutations could influence the effectiveness of various therapeutic agents. For instance, patients with specific KRAS mutations might respond better to certain drugs compared to those with different genetic backgrounds. This distinctly underscores the transition toward personalized medicine, wherein treatments are tailored based on individual genetic composition.
"Understanding the role of KRAS in each patient’s cancer journey can make the difference between treating the disease and merely managing its symptoms."
The Path Ahead for KRAS-targeted Therapies
When we peer into the future, KRAS-targeted therapies seem not only preferable but essential in changing the treatment landscape. Advancements in drug design have yielded agents that specifically inhibit mutant KRAS proteins, showing promise in early clinical trials. The path ahead might be paved with combination therapies, where KRAS inhibitors are used alongside other treatment modalities such as immune checkpoint inhibitors or chemotherapy. Researchers are paving the way to investigate how these combinations might yield synergistic effects.
Moreover, ongoing clinical trials are becoming increasingly important. They serve not just as test beds for innovative treatments but also as platforms for gathering critical data about KRAS mutations in diverse populations. As trials continue to unfold, a clearer picture will emerge regarding which agents work best in tandem with KRAS mutation status.
