Diagnostic Sequencing —
Training activity: 9

Details

Apply the appropriate analytical strategies to solid cancer and haematological malignancy cases

Type

Entrustable training activity (ETA)

Evidence requirements

Evidence the activity has been undertaken by the trainee repeatedly, consistently, and effectively over time, in a range of situations. This may include occasions where the trainee has not successfully achieved the outcome of the activity themselves. For example, because it was not appropriate to undertake the task in the circumstances or the trainees recognised their own limitations and sought help or advice to ensure the activity reached an appropriate conclusion. ​

Reflection at multiple timepoints on the trainee learning journey for this activity.

Considerations

• Filtering strategies
• Tumour normal and driver variants
• National guidance for testing and rationale for selection of testing protocol
• Communication with the tumour board
• Somatic, germline, circulating free DNA and RNA fusion
• Potential patient pathways
• Storage of data in appropriate formats according to local and national standards, taking into consideration patient confidentiality
• Implications for the patient e.g., pharmacogenetic

Reflective practice guidance

The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.

Before action

• What is the objective of applying the correct analytical strategies specifically for cases involving solid cancers and haematological malignancies? What specific analytical pipeline or workflow is used for cancer genomics in your setting, what are the criteria for identifying somatic variants, and how are tumour vs. normal samples (if available) handled?
• Have you analysed genomic data from cancer samples before, and are you familiar with the differences between germline and somatic variant calling? What possible challenges might you face, such as dealing with tumour heterogeneity, low variant allele frequencies, complex genomic rearrangements common in cancer, or interpreting variants in the context of specific cancer types or treatments, and how might you handle them? When would you need to seek advice on challenging cases, variant interpretation in a cancer context, or pipeline problems? How do you feel about applying analytical strategies for cancer genomics?
• What specific skills do you want to develop, such as becoming proficient in a specific cancer analysis pipeline, improving your ability to identify somatic variants accurately, or enhancing your understanding of genomic alterations in different cancer types? What specific insights do you hope to gain into the challenges of cancer genomics analysis, understanding how different analytical steps contribute to identifying therapeutically relevant variants, or appreciating the role of genomics in multidisciplinary cancer care?
• If you’ve worked on cancer cases before, have you reviewed any notes on challenging aspects or areas for improvement in your analysis approach? What important information do you need to consider before embarking on the activity, such as ensuring access to the appropriate analytical tools and pipelines, understanding the specific clinical details for the case including cancer type and sample information (e.g., tumour percentage, paired normal), and reviewing relevant guidelines or best practices for cancer genomics analysis?

In action

• As you are applying analytical strategies for a cancer case, make a note of anything that feels surprising or different from what you anticipate. For example, does a specific somatic variant calling algorithm produce unexpected results, do you encounter a highly complex genomic rearrangement not typically seen, or does the tumour sample show unexpected heterogeneity? Consider how this experience compares with previous experiences of similar activities, such as other genomic data analyses or working with clinical samples. Does it feel more or less familiar, especially regarding the unique challenges of cancer genomics?
• Identify how any unexpected developments, such as a low variant allele frequency or complex genomic alteration, impact your immediate actions. Do you immediately adjust the variant caller parameters, review the sequencing depth in the affected region, or consult with a Genomic Scientist or a multi-disciplinary team member? Do you adapt or change your analytical strategy as a result? For instance, do you decide to incorporate additional external databases for somatic variants, refine your filtering based on tumour purity, or modify your workflow to account for specific cancer subtypes? Do you find it difficult to adapt your analytical approach when faced with the complexities of cancer genomics? Does it affect your confidence in identifying therapeutically relevant variants? Do you feel positive you can reach a successful conclusion?
• Do you recognise when you might need to seek immediate advice or help, such as when a novel somatic variant requires expert clinical correlation or when a complex genomic rearrangement is beyond your current analytical capabilities? Identify what you learn as a result of the unexpected development. For instance, do you learn a new method for detecting low-frequency somatic variants, a specific strategy for interpreting complex rearrangements in cancer, or a more effective way to integrate pathology findings with genomic data?

On action

• Summarise the key steps involved in applying the analytical strategy to the cancer case. Describe the solid cancer or haematological malignancy case you worked on and the specific analytical strategy you applied. Detail the tools or pipelines you used. Were there any specific events, actions, or interactions that felt important during the analysis, such as unexpected findings, challenges specific to cancer genomics (e.g., tumour heterogeneity), or differences between solid tumours and haematological malignancies?
• What specific learning can you take from this cancer analysis? For example, what strengths did you demonstrate in distinguishing somatic vs germline variants or interpreting cancer-specific findings like CNVs or SVs? What skills or knowledge gaps were evident regarding the specific analytical approach, dealing with sample complexities, or interpreting findings in a cancer context? How did this experience compare against previous times you have analysed cancer cases (if any)? Were any previous actions for development in this area achieved? Do you feel your practice has improved? Identify any challenges you experienced, such as dealing with complex rearrangements, low variant allele frequencies, integrating information for reports or interpreting variants with limited evidence in cancer databases, and how you reacted to them. Did these challenges affect your ability to deal with the situation? Were you able to overcome them? Was there anything significant about this activity, such as needing to seek advice or clarification on the analytical strategy or interpretation, or ensuring you were working within your scope of practice?
• Identify the specific actions or ‘next steps’ you will take based on this experience to support your learning. What analytical strategies or approaches will you adjust for future cancer cases? Has anything changed in terms of what you would do if faced with a similar situation again? Do you need to practice specific variant calling techniques, CNV/SV analysis in cancer, or interpreting findings using cancer-specific resources further? How will you assimilate any feedback you received on your analysis?

Beyond action

• Reflect on the solid cancer and haematological malignancy cases you have analysed. Have you revisited your reflections, particularly on cases with complex genomic profiles or uncertain findings? What actions did you previously plan to improve your analytical strategies for cancer cases, such as refining somatic variant filtering, understanding specific cancer pathways, or dealing with tumour heterogeneity? Have you incorporated these improvements into your subsequent analyses? Do you feel prepared to consistently apply a more robust analytical approach for cancer cases based on your past experiences and the steps you’ve taken to improve? Has professional discussion about cancer case analysis or interpretation challenges with senior colleagues provided insights that have changed your approach?
• How has analysing various cancer cases over time developed your capability to select and apply appropriate analytical strategies for solid tumours and haematological malignancies? Do you feel more skilled at identifying clinically relevant somatic variants or structural changes? How does the cumulative learning from analysing cancer cases prepare you for assessments involving variant interpretation in a clinical context, including those specific to cancer? This also feeds into understanding the clinical application and the role of genomics in MDTs. Based on your practice, are you better equipped to identify when a cancer case analysis presents unusual challenges or appears to be beyond your current scope, necessitating consultation or escalation?

Relevant learning outcomes

#	Outcome
# 2	Outcome Evaluate sources of information about variation in the human genome including access, application and clinical impact.
# 3	Outcome Select appropriate tools for next generation sequencing (NGS) analysis of inherited and acquired disease.
# 4	Outcome Analyse NGS data in a clinical setting applying appropriate quality control and data validation.