Fact or Fiction: Ovarian Cancer and Drug Resistance

In ovarian cancer, the emergence of drug resistance has been shown to limit the durability of therapeutic treatment benefit and contribute substantially to ovarian cancer's high mortality rate. Factors such as treatment-free intervals and tumor microevolution may allow for re-sensitization to platinum agents in select patients. In addition to tumor biology, the tumor microenvironment plays a pivotal role in therapeutic resistance. Targeted therapies, once heralded as a solution to chemotherapy resistance, have been shown to face similar obstacles. Drug resistance in ovarian cancer management is an ongoing field of study as clinicians look to limit its impact improve outcomes.
Platinum resistance in ovarian cancer is not always permanent. While many patients relapse with tumors less responsive to platinum-based chemotherapy, resistance can be dynamic. Mechanisms such as epigenetic alterations, modulation of DNA damage response, and temporary activation of drug efflux pumps may contribute to reversible resistance. Importantly, a subset of patients initially labeled as platinum-resistant may benefit from platinum rechallenge after a treatment-free interval, particularly if newer maintenance strategies or resensitizing agents are used. This has led to the concept of a "platinum-free interval" to help guide re-treatment. Understanding these nuances is crucial for tailoring treatment strategies and optimizing outcomes.
Learn more about medications used in ovarian cancer.
While HRD — often due to BRCA1/2 mutations — initially predicts strong sensitivity to DNA-damaging therapies like platinum agents and PARP inhibitors, resistance commonly emerges over time. A key mechanism is the restoration of homologous recombination through secondary or "reversion" mutations in HR pathway genes. These mutations enable tumor cells to resume high-fidelity DNA repair, diminishing the cytotoxic effects of therapy. Additionally, tumors may activate compensatory pathways such as non-homologous end joining or increase drug efflux activity. This resistance may not be detectable at diagnosis and can evolve under therapeutic pressure. Consequently, current research emphasizes longitudinal molecular monitoring to capture evolving resistance mechanisms. Clinically, this underscores the need for re-biopsy or circulating tumor DNA analysis to reassess HR status in recurrent disease, which may influence therapy selection.
Learn more about the importance of biopsy in ovarian cancer.
Tumor heterogeneity — both genetic and phenotypic — plays a central role in drug resistance and further complications treatment outcomes. Ovarian tumors often consist of diverse subclonal populations, some of which may possess innate resistance traits. Within a single ovarian tumor, multiple subclonal populations may coexist, each with distinct characteristics and sensitivity profiles. When systemic therapy is applied, sensitive clones are eliminated, but resistant ones may persist and expand. Single-cell and spatial transcriptomics studies have mapped how this clonal evolution occurs, revealing that treatment can select for resistant subpopulations not evident at baseline. Heterogeneity also affects the tumor microenvironment and immune response, further complicating therapeutic strategies. Clinically, this variability can manifest as mixed responses, where some lesions regress while others progress. Addressing heterogeneity remains a major challenge and has sparked interest in combination therapies and adaptive trial designs. Personalized treatment strategies based on real-time tumor profiling are likely to improve outcomes by accounting for this complexity.
Learn more about ovarian cancer guidelines.
Targeted therapies are susceptible to various resistance mechanisms, many of which overlap with those seen in chemotherapy. For example, resistance to PARP inhibitors, widely used in HRD-positive ovarian cancers, can arise from secondary mutations restoring DNA repair function or through enhanced drug efflux. Similarly, resistance to angiogenesis inhibitors may develop via upregulation of alternative pro-angiogenic pathways or changes in tumor vasculature that circumvent the need for VEGF signaling. Resistance is further complicated by factors such as epigenetic reprogramming and altered cell signaling networks. These findings have led to interest in combining targeted agents with immune checkpoint inhibitors, DNA repair modulators, or epigenetic therapies to overcome resistance. Future success with targeted therapy will likely depend on combination approaches informed by tumor genomics and adaptive resistance profiling.
Learn more about risk assessment and genetic counseling in ovarian cancer.
The tumor microenvironment (TME) is a key contributor to drug resistance in ovarian cancer. Immune cells such as regulatory T cells and tumor-associated macrophages (TAMs) create an immunosuppressive milieu that hinders effective therapy. Additionally, fibroblasts and extracellular matrix components can form physical barriers that limit drug penetration. Cytokines and growth factors secreted within the TME also modulate signaling pathways in tumor cells, promoting survival and resistance. Studies have shown that high TAM density is associated with poor response to both chemotherapy and immunotherapy, and interventions targeting the TME may help reverse resistance. This includes strategies like macrophage reprogramming, TME remodeling agents, and stromal-targeting therapies. Incorporating TME characteristics into clinical decision-making may help guide therapeutic combinations and predict response.
Learn more about tumor biomarkers in ovarian cancer.

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Lumbar spondylitis is a general term for degenerative changes causing pain in the lower spine. It's a progressive condition that can lead to a limited range of motion in your back. Lumbar spondylitis, also called lumbar spondylolysis, can lead to a limited range of motion in the back and problems with other joints, such as the ribs, shoulders, or hips. Symptoms typically develop in early adulthood, but they can also develop in teens or children. Back trauma, chronic repetitive loading, or hyperextension of the back can cause lumbar spondylitis. Ankylosi ng spondylitis is a type of arthritis that can also cause this condition. Ankylosing spondylitis most commonly affects the lower spine. When it involves your lower back, it's sometimes called lumbar spondylitis. This term can also refer to any degenerative changes in your lower spine, such as those caused by osteoarthritis. Symptoms of lumbar spondylitis Lumbar spondylitis symptoms can vary between people. They tend to onset slowly over months to years. The main symptoms are lower back pain and stiffness. Your upper back or neck may also be affected as the condition progresses. Your pain may: get better with exercise, but stay the same or get worse with rest be worse in the morning and evening wake you up at night be felt around your buttocks improve with warmth, such as in a warm shower Pain can range from mild to debilitating. Symptoms tend to flare up and then go through periods where they're reduced or disappear altogether. Other symptoms Other potential symptoms include: pain, stiffness, and warmth in joints, such as the: ribs, which may cause problems with deep breathing shoulders knees hips enthesitis, pain where a bone connects to a tendon abdominal pain and diarrhea loss of appetite weight loss fatigue uveitis, which can cause: vision changes eye pain light sensitivity Lumbar spondylitis causes and risk factors Researchers do not fully understand why some people develop lumbar spondylitis. It's thought that genetic and environmental factors both play a role. People who have the HLA-B27 gene seem to be at an increased risk. More than 90% of people with lumbar spondylitis have this gene. However, most people with this gene never develop lumbar spondylosis. Other risk factors for lumbar spondylitis include: family history age, with most people developing symptoms before age 45 having Crohn's disease being assigned male at birth, occurring about two times more often in males (however, it's believed that AS has been under-recognized and under-diagnosed in biological females) Lumbar spondylitis complications Lumbar spondylitis can compress your spinal cord and lead to neurological symptoms like chronic lower back or leg: pain numbness tingling weakness In rare cases, it can also cause loss of bowel control or loss of bladder control. Other complications can include: reduced joint mobility increased fracture risk increased risk of cardiovascular disease How is lumbar spondylitis treated? Lumbar spondylitis does not have a cure, but a combination of natural remedies, medications, and sometimes surgery can help you slow its progress. Natural remedies and lifestyle modifications Natural remedies or lifestyle modifications that may help you manage your symptoms include: physical therapy, which may include: posture exercises strengthening exercises stretches and mobility work massage exercising regularly focusing on having good posture using assistive devices like walkers or canes minimizing your stress levels eating a nutritious, balanced diet that includes foods like fruits, vegetables, whole grains, and lean protein quitting smoking (this can be difficult, but a doctor can build a cessation plan that works for you) or not starting Medications A doctor may recommend or prescribe the following types of medications: nonsteroidal anti-inflammatory drugs like ibuprofen or celecoxib biologic medications like TNF inhibitors to modify immune system activity janus kinase inhibitors if your condition does not respond to other treatments corticosteroids to decrease inflammation and help with pain (these are used sparingly due to their cumulative side effects) Surgery Because of potential complications, surgery is performed infrequently. Your doctor may recommend surgery if you have trouble with daily activities or neurological complications. Some of the most commonly performed surgeries include: Laminectomy: A laminectomy involves removing a part of the vertebra called the lamina to decompress your spine. Spinal osteotomy: A spinal osteotomy is a procedure used to correct structural abnormalities in your spine. Spinal fusion: Spinal fusion is a procedure where two or more of your vertebrae are permanently fused together. Hip joint replacement: A hip joint replacement involves replacing the ball, socket, or ball and socket of your hip joint with an artificial replacement. When to contact a doctor It's a good idea to contact your primary healthcare professional if you have persistent symptoms that may be a sign of lumbar spondylitis. If your doctor suspects ankylosing spondylitis, they may refer you to a doctor called a rheumatologist who specializes in joints for further evaluation. It's also a good idea to visit your doctor if you've previously been diagnosed with ankylosing spondylitis and you notice a change in your symptoms. How is lumbar spondylitis diagnosed? Lumbar spondylitis can be difficult to diagnose. Doctors will typically consider your personal and family medical history, conduct tests, and order a number of tests to help them make a diagnosis, including: performing a physical exam, which might include: examining your joints watching your movement checking for rib stiffness by having you breathe deeply blood tests to check for inflammation and to see if you have the HLA-B27 gene imaging, such as: X-rays magnetic resonance imaging (MRI) ultrasound You may receive an ankylosing spondylitis diagnosis if you have inflammation in the joints between your lower back and pelvis and at least one of the following symptoms: lower back pain that improves with exercise and gets worse with rest limited movement in your lower back limited ability to expand your chest compared to what would be expected for your age and sex What is the outlook for people with lumbar spondylitis? Lumbar spondylitis generally has a good outlook. There's no cure, and symptoms tend to progress, but in most instances, the condition responds to conservative treatment. Your doctor may recommend surgery if you have neurological complications.