Testing for germline BRCA1/2 mutations has an established predictive role in breast cancer risk assessment. More recently, studies have also identified BRCA1/2 status as clinically relevant in the ...selection of therapy for patients already diagnosed with breast cancer. Emerging breast and ovarian cancer research indicate that BRCA status predicts responsiveness to platinum-based chemotherapy, as well as to inhibitors of poly(ADP-ribose) polymerase (PARP), owing to the ability of these interventions to inhibit DNA repair pathways. BRCA1/2 mutation testing thus has important and expanding roles in treatment planning for subsets of patients with breast cancer. Recent studies have demonstrated different activity of platinum salts in BRCA-mutated compared with non-BRCA-mutated breast cancer. Furthermore, phase II/III studies of single-agent PARP inhibitors (PARPi) have shown encouraging progression-free survival results in patients with BRCA1/2-mutated breast cancer, which led to the recent approval of olaparib, the first PARPi to be approved in breast cancer. Determining BRCA1/2 mutation status in this breast cancer subgroup could potentially expand treatment options beyond the current standard of taxane and anthracycline-based chemotherapy. Although attempts have been made to develop scoring systems that measure defects in homologous recombination repair pathways to predict response to platinum or PARPi, none have yet made it into clinical use. In this review, we summarise the recent and ongoing preclinical and clinical studies on the treatment of BRCA-associated breast cancer, and discuss efforts to identify other breast cancer patients who may be responsive to therapies effective in BRCA mutation carriers, including platinum-containing chemotherapy and PARPi.
Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and ...BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exposure to traumatic stress is associated with increased risk for posttraumatic stress disorder (PTSD) and alterations of hypothalamic–pituitary–adrenocortical (HPA) function. Research linking ...traumatic stress with HPA function in PTSD has been inconsistent, however, in part due to (a) the inclusion of trauma-exposed individuals without PTSD (TE) in control groups and (b) a failure to consider comorbid major depressive disorder (MDD) and moderating variables. This meta-analysis of 47 studies (123 effect sizes, N=6008 individuals) revealed that daily cortisol output was lower for PTSD (d=−.36, SE=.15, p=.008) and PTSD+MDD (d=−.65, SE=.25, p=.008) groups relative to no trauma controls (NTC); TE and NTC groups did not differ significantly from each other. Afternoon/evening cortisol was lower in TE (d=−.25, SE=.09, p=.007) and PTSD (d=−.27, SE=.12, p=.021) groups and higher in PTSD+MDD groups (d=.49, SE=.24, p=.041) relative to NTC. Post-DST cortisol levels were lower in PTSD (d=−.40, SE=.12, p<.001), PTSD+MDD (d=−.65, SE=.14, p<.001), and TE groups (d=−.53, SE=.14, p<.001) relative to NTC. HPA effect sizes were moderated by age, sex, time since index event, and developmental timing of trauma exposure. These findings suggest that enhanced HPA feedback function may be a marker of trauma-exposure rather than a specific mechanism of vulnerability for PTSD, whereas lower daily cortisol output may be associated with PTSD in particular.
► Daily cortisol output was lower for PTSD and PTSD+MDD groups relative to NTC. ► No significant differences between TE and NTC groups in daily cortisol output. ► Afternoon cortisol was lower in PTSD groups relative to NTC. ► Afternoon cortisol was higher in PTSD+MDD groups relative to NTC. ► Post-DST cortisol levels were lower in PTSD, PTSD+MDD, TE groups relative to NTC.
PARP inhibitors have been approved for the treatment of metastatic breast cancer in germline BRCA mutation (gBRCAm) carriers. The recent OlympiA trial demonstrated improved progression-free and ...distant disease-free survival with adjuvant olaparib for gBRCAm carriers with HER2-negative high-risk early-stage breast cancer. The current article addresses some for the questions raised by OlympiA regarding how to incorporate PARP inhibitors into the treatment of early-stage breast cancer as well as future directions for PARP inhibitors in breast cancer treatment and prevention.
Among patients who had mutations in
BRCA1
or
BRCA2
and were at high risk for disease progression, those who were assigned to a year of olaparib adjuvant therapy had 3-year invasive disease–free ...survival of 86%, as compared with 77% among those who were assigned to placebo. Few patients stopped olaparib owing to side effects.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline ...(g)
/
mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)
/
mutations or g/s mutations in homologous recombination (HR)-related genes other than
2.
Eligible patients had MBC with measurable disease and germline mutations in non-
/
HR-related genes (cohort 1) or somatic mutations in these genes or
/
(cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in
s
/
,
or
. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g
(ORR, 82%) and s
/
(ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable NA) for g
and 6.3 months (90% CI, 4.4 months to NA) for s
/
mutation carriers. No responses were observed with
or
mutations alone.
PARP inhibition is an effective treatment for patients with MBC and g
or s
/
mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g
/
mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
Clin Psychol Sci Prac 17: 293–306, 2010
The high level of concurrent and sequential comorbidity between anxiety and depression in children and adolescents may result from (a) substantial overlap in ...both the symptoms and items used to assess these putatively different disorders, (b) common etiologic factors (e.g., familial risk, negative affectivity, information‐processing biases, neural substrates) implicated in the development of each condition, and (c) negative sequelae of anxiety conferring increased risk for the development of depression. Basic research on their various common and unique etiologic mechanisms has guided the development of efficacious treatments for anxiety and depressive disorders in youth. Potential processes through which the successful treatment of childhood anxiety might prevent subsequent depression are described.
ABSTRACT
Since its description by Li and Fraumeni over 40 years ago, Li–Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are ...affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association with TP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multigene assessments of individuals at increased cancer risk, which have already begun to identify those with very little personal or family cancer history carrying germline TP53 mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention, and management. Finally, we observe how the clinical criteria for TP53 mutation screening appear to be evolving as our understanding of the impact of germline TP53 mutations continues to expand.
This review highlights Li–Fraumeni syndrome, the familial cancer predisposition syndrome that affects both children and adults, and its association with germline TP53 mutations. Classic and evolving definitions of the syndrome are discussed, highlighting the potential implications that multi‐gene analysis may have in expanding our understanding of how phenotype and genotype correlate. Newer options for clinical management of individuals at risk are also discussed.
Summary Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA -deficient cells. A maximum tolerated dose and initial signal of ...efficacy in BRCA -deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov , number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 41%; grade 3 or 4, four 15%), nausea (grade 1 or 2, 11 41%; grade 3 or 4, four 15%), vomiting (grade 1 or 2, three 11%; grade 3 or 4, three 11%), and anaemia (grade 1 or 2, one 4%; grade 3 or 4, three 11%). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 41%; none grade 3 or 4) and fatigue (grade 1 or 2, seven 26%; grade 3 or 4, one 4%). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA -deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1 -associated or BRCA2 -associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. Funding AstraZeneca.
In postmenopausal women at increased risk for breast cancer, exemestane reduced the annual incidence of invasive breast cancer by 65% after a median follow-up of only 3 years. Exemestane caused no ...serious toxic effects and only minimal changes in quality of life.
Estrogens contribute to normal breast development but can also promote breast cancer in preclinical models and in women with high circulating plasma estrogen levels.
1
–
4
To date, chemoprevention of breast cancer has focused on the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene, which exert antiestrogenic effects on the breast, as well as agonist or antagonist effects on other organs. In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, tamoxifen significantly reduced the number of invasive breast cancers, by 49% (P<0.001) as compared with placebo.
5
A meta-analysis of trials comparing tamoxifen with placebo showed that tamoxifen reduced the incidence . . .
PDF
