This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the effects of risk‐reducing mastectomy on unaffected women with a strong family history of breast ...cancer with a specific focus on breast cancer incidence, psychosocial outcomes (including satisfaction with decision and cosmetic outcomes), surgical complications, and mortality.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess whether the sequence in which anthracyclines and taxanes are administered, in an adjuvant or ...neoadjuvant setting, affects outcomes in women with early breast cancer.
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the effects of platinum‐based chemotherapy as adjuvant and neoadjuvant treatment for patients with ...early triple negative breast cancer
Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer ...predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability. Keywords: Familial cancer, Genetics, Variants, Whole-genome sequencing, Diagnostic testing, Health economics
Fear of cancer recurrence (FCR) affects 50%-70% of cancer survivors. This multicenter, single-arm study sought to determine the participant-rated usefulness of an oncologist-delivered FCR ...intervention.
Women who completed treatment for early breast cancer (could be receiving endocrine therapy) with baseline FCR > 0 were invited to participate. FCR was measured using a validated 42-item FCR Inventory. The brief oncologist-delivered intervention entailed (1) FCR normalization; (2) provision of personalized prognostic information; (3) recurrence symptoms education, (4) advice on managing worry, and (5) referral to psycho-oncologist if FCR was high. FCR, depression, and anxiety were assessed preintervention (T0), at 1 week (T1), and 3 months (T2) postintervention. The primary outcome was participant-rated usefulness. Secondary outcomes included feasibility and efficacy.
Five oncologists delivered the intervention to 61/255 women invited. Mean age was 58 ± 12 years. Mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three women (71%) were on adjuvant endocrine therapy. Of 58 women who completed T1 assessment, 56 (97%) found the intervention to be useful. FCR severity decreased significantly at T1 (F = 18.5, effect size = 0.39,
< .0001) and T2 (F = 24, effect size = 0.68,
< .0001) compared with baseline. There were no changes in unmet need or depression or anxiety. Mean consultation length was 22 minutes (range, 7-47 minutes), and mean intervention length was 8 minutes (range, 2-20 minutes). The intervention was perceived as useful and feasible by oncologists.
A brief oncologist-delivered intervention to address FCR is useful and feasible, and has preliminary efficacy in reducing FCR. Plans for a cluster randomized trial are underway.
This study aims to determine the attitudes and barriers of Australian oncology health professionals towards using tamoxifen as a breast cancer risk‐reducing medication (RRM). Our target group was ...health professionals involved in breast cancer risk assessment or treatment. Members of relevant medical organizations in Australia and New Zealand were invited to participate in a web‐based survey assessing: their attitudes towards tamoxifen as a RRM; which health professionals they felt were responsible for initiating and monitoring women on RRM and their views on workforce issues related to RRM prescription. There were 100 respondents, including 33 genetic health professionals, 32 medical oncologists and 20 surgeons. Respondents perceived tamoxifen to be effective as a RRM (99%). However, only 41% of prescribing health professionals (n = 64) had ever prescribed tamoxifen as a RRM. Overall, survey respondents felt that the initiation of RRM was the role of specialists. Assessing a patient's risk of breast cancer was reported to be the role of cancer geneticists/familial cancer clinicians (74%) and medical oncologists (66%). Discussion about the use of RRM was reported to be the role of these same groups (84% and 85% respectively). Medical oncologists (83%) and breast physicians (70%) were most frequently considered to be responsible for initiating the prescription and monitoring women once commenced on RRM (72% and 71% respectively). Oncology health professionals express confidence in the effectiveness of tamoxifen as a RRM despite reporting low prescription rates. Findings demonstrate that these oncology health professionals felt that initiation of RRM was the role of cancer specialists, despite preventative medicine being seen as a primary care activity. If uptake among at‐risk women increases, this will put a significant burden on cancer services and GPs will need to take on a greater role in the delivery of RRM.
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated ...for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6x
, 9x
, 6x
, 4x
), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an
exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (
) mutations.
EMBRACA (NCT01945775) was a randomized ...phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician's choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline
(g
) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) or triple-negative breast cancer (TNBC) subgroups.
Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2-: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2- and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia.
Across all patient subgroups with g
-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.
The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these ...results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies.
We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy.
A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR.
Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.
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