Surprising Insights on Ovarian Cancer Treatment (ESMO 2024)
The ESMO Gynaecological Cancers Congress, one of the most anticipated events in the oncology calendar, recently concluded in Florence, Italy. This event, known for its critical updates and breakthroughs in gynaecological cancer treatment, did not disappoint. Here are some of the key insights and discussions from the congress.
Did you know?
Successfully removing all visible tumours in ovarian cancer surgery can add 2.5 to 5 extra years to a patient’s life.
Surgical expertise matters! Getting surgery at specialised centres can significantly improve survival rates for ovarian cancer patients.
Healthcare Postcode Lottery is a thing… In the UK, where you live can drastically affect your treatment outcomes due to variations in surgical practices. So head to your GP and demand a referral to a specialised centre!
Rapid BRCA testing could contribute to timely treatment decisions and improving patient outcomes, but it currently takes way too long to get the results.
Half of BRCA-mutated ovarian cancer patients don’t benefit from PARP inhibitors due to various resistance mechanisms. Key lesson: look beyond BRCA.
Hyperthermic Intraperitoneal Chemotherapy (HIPEC) therapy shows promise in treating ovarian cancer when combined with surgery.
Low-Grade Serous Carcinoma: This rare subtype of ovarian cancer requires different treatments due to its unique genetic markers.
The term “platinum-resistant” may soon be replaced with “platinum-ineligible” to better describe patient responses.
Antibody-Drug Conjugates (ADCs) are emerging as the magic bullet for targeted cancer treatment, reducing damage to healthy tissues while attacking cancer cells. But there are still so many challenges ahead…
Telesurgery, enhanced by AI and haptic feedback, could provide expert surgical care to patients anywhere in the world.
Why Doctors Struggle to Provide Optimal Care
Doctors want the best for their patients (that’s why they became doctors! ), but they’re often restricted by a chain of obstacles:
Regulatory Approvals: Local and international regulatory bodies set the standards, influenced by regional health policies and geography, impacting economic factors.
Economic Factors: Healthcare funding and budgets dictate treatment availability, shaping the design and scope of clinical trials.
Clinical Trial Outcomes: Economic constraints influence trial designs, which are driven by pharmaceutical companies and clinicians’ collaboration priorities.
Trial Design: Pharmaceutical priorities are driven by profitability, affecting the focus and resources allocated to treatments.
Pharmaceutical Priorities: Companies navigate different healthcare systems (public vs. private), impacting treatment implementation and accessibility.
Healthcare Systems: These systems limit the ability to address unmet medical needs, which doctors strive to improve.
Get the gist? 🌍🔬💊
For your information: The standard of care for advanced ovarian cancer typically includes surgery to remove as much of the tumour as possible, followed by chemotherapy with platinum-based drugs like cisplatin or carboplatin (types of chemotherapy drugs that contain platinum and are used to kill cancer cells), often combined with paclitaxel (a chemotherapy drug that stops cancer cell growth). Additionally, targeted therapies such as PARP inhibitors (drugs that block an enzyme used by cancer cells to repair DNA) or Bevacizumab (a drug that inhibits the growth of blood vessels that supply tumours) may be included, depending on the patient's genetic profile and response to treatment.
Photo credit: https://www.producthunt.com/products/mermaid-chart
Information adapted from Giovanni Scambia, ESMO 2024
Surgical Excellence: The Key to Longer Survival
Philipp Carter’s presentation was a highlight, emphasizing that complete tumour resection (surgical removal) remains the gold standard in advanced ovarian cancer surgery. He shared a retrospective study (study that looks back at data from the past) that starkly illustrated disparities in treatment outcomes across different UK cancer centres, highlighting the importance of surgical expertise and specialised centres in improving patient outcomes. The study compared outcomes for patients with advanced epithelial ovarian cancer (EOC) treated at two neighbouring UK cancer centres (A and B) and found significant differences in practice and outcomes. Key differences included:
Surgical Rates: Patients at centre A were more likely to undergo surgery compared to those at centre B (87% vs. 59.8%).
Tumour Burden and Complexity: The median surgical complexity score was significantly higher at centre A compared to centre B (9 vs. 2).
Survival Rates: Center A had a higher rate of total macroscopic (anything that can be seen) tumour clearance (84.7% vs. 58.9%) and better overall survival rates compared to centre B.
Hospital Stays and Operation Times: Centre A had longer median operation times and hospital stays compared to centre B, reflecting more complex surgeries.
These variations highlight that treatment outcomes for similar conditions can differ significantly based on location, suggesting a disparity in healthcare quality and access within the UK's NHS. This underscores a critical message for patients: choosing a treatment centre with a proven track record in complete cytoreduction (complete removal of the tumour) can be a matter of life and death.
The Debate: Surgery vs. Chemotherapy
One of the more contentious topics was the role of upfront surgery versus Neo-adjuvant Chemotherapy (NACT). “Neoadjuvant" refers to treatments given as a first step to shrink a tumour before the main treatment, usually surgery, is performed.
The consensus? Upfront surgery still holds the upper hand, especially for BRCA wild-type cancers, as NACT can potentially induce resistance to platinum-based therapies. Antonio Gonzalez-Martin and Kathleen Moore stressed the importance of rapid BRCA testing, advocating for a turnaround time of just one week to make timely treatment decisions. The historical rationale was discussed, noting that the effect of surgery diminishes with the number of chemotherapy cycles in NACT. “If it’s true that we’re harming patients with BRCA (wt) with NACT, then we should 100% stop doing that. But they have to get the BRCA test back in a week,” said Kathleen. Additionally, cancers challenged with platinum NACT prior to primary debulking surgery (PDS) could acquire therapy resistance mechanisms, worsening prognosis.
Interval Debulking Surgery (IDS), as opposed to Primary Debulking Surgery (PDS), is not a standard solution for the problem of residual tumours in ovarian cancers and should not be used to hide “double left hand syndrome.” Clinical trial data is awaited to elucidate best practices.
Fragility Risk Factors
Clinicians must consider fragility risk factors that might indicate perioperative complications. "Perioperative" refers to the period surrounding a patient's surgical procedure. It encompasses three phases: preoperative, intraoperative, and postoperative.
Did you know that 23% of advanced ovarian cancer (AOC) patients fail primary standard therapy and relapse within a year? This highlights the urgent need to identify pre-op comorbidities and risk factors that might indicate surgical complications.
Addressing Platinum Resistance
Frederik Marmé’s session on platinum-resistant ovarian cancer (a type of ovarian cancer that does not respond to platinum-based chemotherapy) shed light on the complexities of treating this aggressive form of the disease. Platinum resistance mechanisms are diverse, including drug-efflux pumps (proteins that pump chemotherapy drugs out of cancer cells) and DNA repair protein up-regulation (increased production of proteins that repair damaged DNA in cancer cells). New strategies, such as targeting specific pathways and vulnerabilities, are being explored to overcome this resistance. Nicoletta Colombo suggested moving away from the term "platinum-resistant" to "platinum-ineligible" to better reflect the continuum of patient responses.
Challenges and Innovations in Molecular Diagnosis
Antonio Gonzalez-Martin presented on the four pillars of treatment: surgery, molecular diagnosis (identifying specific genetic and molecular characteristics of the tumour), chemotherapy, and PARP inhibitor maintenance (ongoing treatment to prevent cancer recurrence). Molecular diagnosis continues to be a cornerstone in the treatment of advanced ovarian cancer. Antonio pointed out a critical gap: the lack of reliable biomarkers (biological indicators) for selecting patients for Bevacizumab, a drug that inhibits angiogenesis (the formation of new blood vessels that supply the tumour). While KELIM (a score that predicts response to chemotherapy) can help select patients who may benefit most from Bevacizumab, confirmation in randomised clinical trials is eagerly awaited. The anticipation surrounding the results of the NIRVANA and AGO-OVAR 28 trials, which could provide much-needed clarity, was palpable.
Understanding PARP Inhibitor Resistance
A significant challenge in treating ovarian cancer is resistance to PARP inhibitors (drugs that block an enzyme cancer cells use to repair DNA). Antonio's discussion on the mechanisms of resistance was eye-opening. Did you know that 50% of BRCA-mutated (genetic mutation associated with higher cancer risk) patients do not benefit from PARP inhibitors? This resistance is often due to the restoration of homologous recombination (a DNA repair process), mitigation of replication stress (reducing problems during DNA replication), drug efflux transporters (proteins that pump drugs out of cells), and BRCA reversion mutations (mutations that reverse the original BRCA mutation). The search for better biomarkers (biological indicators), functional HRD tests (tests that assess homologous recombination deficiency), and the development of next-generation PARP inhibitors were highlighted as critical areas of ongoing research.
Selection Criteria for PARPi and Bevacizumab
Antonio discussed how to select HRD patients for PARPi+Bevacizumab versus PARPi alone. Platinum sensitivity is suggested as a surrogate marker for PARPi, with highly sensitive patients receiving PARPi alone and resistant patients receiving Bevacizumab alone. Criteria include favorable KELIM scores, near complete response by RECIST, and high CRS if NACT. However, there’s no perfect correlation between KELIM, RECIST, or CRS, so patients need to be evaluated case by case.
New Populations with Unmet Needs
New patient populations with unmet clinical needs were identified:
HRD positive (homologous recombination deficiency) patients progressing during PARPi treatment: These patients do worse than those progressing after PARPi.
HRD negative (homologous recombination proficiency) patients: What treatment to give them since they don't respond well to PARPi? Current focus is on the Antibody-Drug Conjugates (ADCs) space with seven trials in process and the potential of WEE1 inhibitors and CDK2 inhibitors.
Future of HRD Testing
Current HRD tests have limitations, including costs, availability, and a binary classification of a continuous variable. Issues like tissue quality, tumour selection, and ignoring tumour evolution (spatial and temporal heterogeneity) affect test reliability.
Good news: we're developing a comprehensive functional HRD assay to overcome current limitations.
Contact me for details.
Proffered Papers: Breakthroughs and Ongoing Trials
Several proffered papers presented at the congress showcased cutting-edge research and clinical trials. Notably, the MIRASOL trial demonstrated the efficacy of mirvetuximab soravtansine in platinum-resistant ovarian cancer, positioning it as the new standard of care for patients with high folate receptor-alpha expression. Additional significant trials include the DUO-O study, which showed a progression-free survival (PFS) benefit with durvalumab + chemotherapy + bevacizumab followed by durvalumab, bevacizumab, and olaparib maintenance in HRD-positive (homologous recombination deficiency) patients.
The Promise of Telesurgery
One of the most exciting prospects discussed was the future of telesurgery. Giovanni Scambia presented on the potential to democratise access to expert surgical care globally. By integrating artificial intelligence and machine learning, telesurgery could ensure that patients in remote locations receive the same quality of care as those in top-tier medical centres. Haptic feedback systems will allow surgeons to feel tissue textures even when operating from miles away, potentially revolutionising surgical precision and patient outcomes.
Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Jean-Marc Classe highlighted the potential of HIPEC in treating ovarian cancer. Despite the current lack of robust trial data, HIPEC could be a valuable option, particularly in first-line treatment at interval surgery and in first relapse treatment after six cycles of second-line chemotherapy. Standardizing HIPEC protocols will be crucial to its broader adoption and success.
Low-Grade Serous Carcinoma: A Unique Challenge
Low-grade serous carcinoma (LGSOC), a rare subtype of ovarian cancer, presents unique challenges. Anais Malpica emphasized that LGSOC has a low mitotic index and distinct genetic markers, necessitating different therapeutic approaches compared to high-grade serous ovarian cancer (HGSOC). Complete resection at primary debulking surgery remains the most important prognostic factor, once again underscoring the need for specialised surgical teams. Fabrice Lecuru pointed out that patients are younger at diagnosis of LGSOC compared to HGSOC and also stressed the importance of sending patients to expert centres to achieve complete resection.
Antibody-Drug Conjugates (ADCs): A Promising Frontier
Toon Van Gorp's discussion on ADCs highlighted their potential as a "magic bullet" in cancer treatment. ADCs aim to reduce off-target toxicities by delivering cytotoxic drugs directly to cancer cells. However, challenges remain, including patient selection, managing adverse events, and addressing resistance. Despite these hurdles, ADCs like mirvetuximab soravtansine are showing promise in clinical trials.
Future Directions in Clinical Trials
The congress also emphasised the need for better-designed clinical trials. Mixed responses during the Q&A sessions underscored the importance of considering HRD status and other biomarkers in trial designs. The consensus was clear: more functional markers and comprehensive testing are needed to tailor treatments effectively. Christina Fotopoulou remarked that clinical trials should account for tumour biology, not just stage and tumour burden.
Conclusion: A Bright Future Ahead
The ESMO Gynaecological Cancers Congress 2024 highlighted significant advancements in the treatment of ovarian cancer. From surgical innovations to emerging therapies and the potential of AI and radiomics, the future looks promising. As we continue to push the boundaries of science and medicine, the ultimate goal remains clear: improving patient outcomes and extending lives.
For more detailed information on the studies and data presented at the congress, visit the ESMO website.
Additional Resources
Annals of Oncology: For detailed studies and clinical trial results, check the Annals of Oncology.
Cancer Treatment Reviews: Explore more about the mechanisms of drug resistance in ovarian cancer on Cancer Treatment Reviews.
Precision Oncology: Learn about the latest advancements in genomic testing and personalised treatment approaches on Precision Oncology.
Disclaimers:
* I’m a scientist, not a clinician.
** My personal notes should be largely correct, though I'm only human!
Join the dialogue—reflect, share your tales from the trenches, and by all means correct me if you spot any erroneous information.
