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- Engvall, Kristina, 1978-
(författare)
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Taxane-Induced Peripheral Neuropathy among Early-Stage Breast Cancer Survivors : Prevalence, Risk Factors, Quality of Life and Genetic Prediction Models
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Taxane-induced peripheral neuropathy (TIPN) is a common and distressful side effect. Little is known on how long TIPN persist and its effect on health-related quality of life (HRQL). The overall aim of this thesis was to study the prevalence and severity of persistent TIPN, to investigate its impact on HRQL and to explore the clinical and genetic risk factors for TIPN among early-stage breast cancer survivors (ESBCS). Methods: A population-based cohort of 884 recurrence-free ESBCS diagnosed 2010-2015 in the Southeast Health Care region, Sweden and 1768 control women without prior cancer, who received a postal questionnaire including EORTC chemotherapy-induced peripheral neuropathy (CIPN20) and QLQ-C30 instruments. Prevalence of TIPN symptoms and clinical risk factors were explored. Adjusted relative risks (RR) were estimated for ESBCS compared to control women. For impact on HRQL, adjusted mean scores of QLQ-C30 scales among ESBCS with and without TIPN were calculated. Blood samples from 362 ESBCS were whole-exome sequenced. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training and test cohort. Results: The response rate was 79% for ESBCS and 59% for controls. The median time post-taxane was 3.6 years. The adjusted RR for ESBCS vs. controls was highest (RR 1.8) for tingling in feet and numbness in feet. Individual sensory symptoms occurred in 9%-48% and motor symptoms in 7%-61% of ESBCS. The most prevalent symptoms were difficulty opening jar and cramps in feet. Paclitaxel, older age, overweight, diabetes mellitus, vibrating hand tools, smoking and autoimmune disease were independent risk factors (Study I). All 13 sensory and motor TIPN symptoms at increased risks among ESBCS had a significant impact on global health status, which worsened with increased severity of TIPN. Between 30%-93% of ESBCS with moderate-severe TIPN reported a clinically important impairment of functioning and personal finances. Moderate-severe difficulty climbing stairs and problems standing/walking were associated with medium-large clinically important differences (Study II). In the explorative sub-study, two of five prediction models based on genetic and clinical risk factors obtained AUC results above 60% in the test cohort. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted (Study III).Conclusions: Most sensory and motor symptoms are more common among taxane-treated ESBC survivors than in women from the general population, many symptoms persist ≥3.6 years. Persistent TIPN symptoms are associated with clinically relevant impairment of HRQL. Polygenic prediction models including clinical risk factors may be used to estimate the risk of persistent taxane-induced numbness in feet and tingling in feet.
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| 2. |
- Loman, Niklas
(författare)
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Clinical Aspects of Hereditary Breast Cancer
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A positive family history of breast cancer (BC) is one of the strongest predictors of the disease. Two major BC susceptibility genes, BRCA1 and BRCA2 were identified about a decade ago. In this thesis, studies of different biological. clinical and epidemiological aspects of hereditary BC are presented. In the first paper data on the expression of steroid hormone receptors in hereditary BC are presented. We confirm previously published data regarding the paucity of estrogen and progesterone receptors in BRCA1-associated BC, and report new findings in BRCA2-associated tumours and cases with an unidentified hereditary factor. Hormone receptor levels in these two groups do not differ significantly from each other or from an age-matched control population unselected for family history. The second paper is a cohort study of cancer incidence in relatives of BRCA1 and BRCA2 germline mutation carriers. Other cancers than BC and ovarian cancer do not appear to be greatly increased and require specific follow-up in carriers. The third study is a retrospective case-control study on the prognosis and clinical presentation of BRCA2-associated BC. BC in families with an identified BRCA2 mutation seemed to present at a more advanced stage at diagnosis compared with age and year of diagnoses matched controls. This translated into an increased risk to die from BC in this group, but overall survival was not significantly decreased. The fourth study is a population-based study of family history and BRCA1 and BRCA2 mutations in BC cases below the age of 41. A positive family history was very frequent in this group of young BC patients. About one-third of them had a family history including at least one first- or second-degree relative with BC. A positive BRCA1-mutation status was observed in 6.8% of the cases, and BRCA2-mutations were seen in 2.1% of the in women. BRCA1 and BRCA2 mutations were more prevalent in younger women, in women with a positive family history including at least one first-degree relative with breast or ovarian cancer, and in women that had already or did develop a bilateral BC during a median follow-up of 5.5 years. In the fifth study relative and cumulative cancer incidence in the first-degree relatives of the woman of the previous study were calculated and compared with the population. The BC risk was still increased in first-degree relatives of women with early-onset BC (below the age of 41) when BRCA-mutation carriers were excluded, in addition an association with prostate cancer was suggested. The risk of prostate cancer did only appear to be increased in relatives of women with BC below the age of 36. Furthermore, cumulative BC incidences were calculated for women with different hereditary backgrounds.
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