DNA sequencing of tumour tissue has become the standard care for many solid cancers because of the option to detect somatic variants that have significant therapeutic, diagnostic and prognostic ...implications. Variants found within the tumour may be either somatic or germline in origin. Somatic cancer gene panels are developed to detect acquired (somatic) variants that are relevant for therapeutic or molecular characterisation of the tumour, expanding gene panels now include genes which may also inform patient management such as cancer predisposition syndromes (CPS) genes. Identifying germline cancer predisposition variants can alter cancer management, the risk of developing new primary cancers and risk for cancer in at-risk family members. This paper discusses the clinical, technical and ethical challenges related to identifying and reporting potential germline pathogenic variants that are detected on tumour sequencing. It also highlights the existence of the eviQ national guidelines for CPS with advice on germline confirmation of somatic findings to pathology laboratories in Australia.
Background
Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of the cancer returning. In early TNBC, ...platinum‐based chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long‐term survival outcomes has not been fully elucidated and recommendations to include platinum chemotherapy are not consistent in international guidelines.
Objectives
To evaluate the benefits and harms of platinum‐based chemotherapy as adjuvant and neoadjuvant treatment in people with early triple‐negative breast cancer.
Search methods
We used standard, extensive Cochrane search methods. The latest search date was 4 April 2022.
Selection criteria
We included randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC.
Data collection and analysis
We used standard Cochrane methods. Our primary outcomes were disease‐free survival (DFS) and overall survival (OS). Our secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. Prespecified subgroups included BRCA mutation status, homologous recombination deficiency (HRD) status, frequency of chemotherapy, type of platinum agent used, and the presence or absence of anthracycline chemotherapy. We assessed risk of bias using Cochrane's RoB 1 tool and certainty of evidence using the GRADE approach.
Main results
From 3972 records, we included 20 published studies involving 21 treatment comparisons, and 25 ongoing studies. For most domains, risk of bias was low across studies. There were 16 neoadjuvant chemotherapy studies (one of which combined neoadjuvant and adjuvant therapy) and four adjuvant chemotherapy trials. Most studies used carboplatin (17 studies) followed by cisplatin (two), and lobaplatin (one). Eight studies had an anthracycline‐free intervention arm, five of which had a carboplatin‐taxane intervention compared to an anthracycline‐taxane control.
All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS in neoadjuvant and adjuvant settings (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; 7 studies, 8 treatment comparisons, 1966 participants; high‐certainty evidence; adjuvant: HR 0.69, 95% CI 0.54 to 0.88; 4 studies, 1256 participants; high‐certainty evidence). Platinum chemotherapy in the regimen improved OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; 7 studies, 8 treatment comparisons, 1973 participants; high‐certainty evidence; adjuvant: 0.70, 95% CI 0.50 to 0.96; 4 studies, 1256 participants; high‐certainty evidence). Median follow‐up for survival outcomes ranged from 36 to 97.6 months.
Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59; 15 studies, 16 treatment comparisons, 3083 participants; high‐certainty evidence). Subgroup analyses showed no evidence of differences in DFS according to BRCA mutation status, HRD status, lymph node status, or whether the intervention arm contained anthracycline chemotherapy or not.
Platinum chemotherapy was associated with reduced dose intensity, with participants more likely to require chemotherapy delays (RR 2.23, 95% CI 1.70 to 2.94; 4 studies, 5 treatment comparisons, 1053 participants; moderate‐certainty evidence), dose reductions (RR 1.77, 95% CI 1.56 to 2.02; 7 studies, 8 treatment comparisons, 2055 participants; moderate‐certainty evidence) and early cessation of treatment (RR 1.20, 95% CI 1.04 to 1.38; 16 studies, 17 treatment comparisons, 4178 participants; moderate‐certainty evidence). Increased haematological toxicity occurred in the platinum group who were more likely to experience grade III/IV neutropenia (RR 1.53, 95% CI 1.43 to 1.63; 19 studies, 20 treatment comparisons, 4849 participants; moderate‐certainty evidence), anaemia (RR 8.20, 95% CI 5.66 to 11.89; 18 studies, 19 treatment comparisons, 4757 participants; moderate‐certainty evidence) and thrombocytopenia (RR 7.59, 95% CI 5.10 to 11.29; 18 studies, 19 treatment comparisons, 4731 participants; moderate‐certainty evidence). There was no evidence of a difference between chemotherapy groups in febrile neutropenia (RR 1.16, 95% CI 0.89 to 1.49; 11 studies, 3771 participants; moderate‐certainty evidence). Renal impairment was very rare (0.4%, 2 events in 463 participants; note 3 studies reported 0 events in both arms; 4 studies; high‐certainty evidence). Treatment‐related death was very rare (0.2%, 7 events in 3176 participants and similar across treatment groups; RR 0.58, 95% 0.14 to 2.33; 10 studies, 11 treatment comparisons; note 8 studies reported treatment‐related deaths but recorded 0 events in both groups. Thus, the RR and CIs were calculated from 3 studies rather than 11; 3176 participants; high‐certainty evidence). Five studies collected quality of life data but did not report them.
Authors' conclusions
Platinum‐based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long‐term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity, though serious adverse events including neuropathy, febrile neutropenia or treatment‐related death were not increased.
These findings support the use of platinum‐based chemotherapy for people with early TNBC. The optimal dose and regimen are not defined by this analysis, but there is a suggestion that similar relative benefits result from the addition of carboplatin to either anthracycline‐free regimens or those containing anthracycline agents.
As demand for germline genetic testing for cancer patients increases, novel methods of genetic counseling are required. One such method is the mainstream consent pathway, whereby a member of the ...oncology team (rather than a genetic specialist) is responsible for counseling, consenting, and arranging genetic testing for cancer patients. We systematically reviewed the literature for evidence evaluating mainstream pathways for patients with breast, ovarian, colorectal, and prostate cancer. Medline, EMBASE, and Cochrane Library were searched for studies that met inclusion and exclusion criteria. Article references were checked for additional studies. Trial databases were searched for ongoing studies. Of the 13 papers that met inclusion criteria, 11 individual study groups were identified (two study groups had two publications each). Ten of the 11 studies evaluated the acceptability, feasibility, and impact of BRCA testing for patients and/or clinicians in different clinical settings in breast and ovarian cancer, while the final study explored the attitudes of colorectal specialists toward genetic testing for colorectal cancer. None involved prostate cancer. Overall, mainstream pathways were acceptable and feasible. Medical oncologist‐ and nurse‐driven pathways were particularly successful, with both patients and clinicians satisfied with this process. Although the content of pretest counseling was less consistent compared with counseling via the traditional model, patients were largely satisfied with the education they received. Further research is required to evaluate the mainstream pathway for men with prostate cancer.
Germline genetic testing results can guide treatment decisions for oncology patients and are now offered to many cancer patients. Mainstream testing refers to genetic testing arranged by a ...non-genetics specialist. This repeated cross-sectional study aimed: (1) to capture clinician views on the existing mainstreaming genetic testing program for ovarian, breast, prostate, and endometrial cancer patients, and (2) to ascertain the interest of clinicians to consider changing practice to adopt mainstream testing.
Mainstreaming has occurred since 2015 for patients with ovarian and some breast cancer patients, expanding to include prostate cancer patients in 2019, and endometrial cancer patients in 2020. Two web-based surveys were administered within two health districts, covering seven hospitals in NSW.
Fifty-four clinicians (70% response rate) participated. Clinicians who had arranged mainstream genetic testing (n = 30) were overall satisfied (76%), viewed the process as time-efficient and accessible for patients, and desired continuation of the program. Of those clinicians yet to engage in the program (n = 24), 88% expressed an interest in learning about mainstream testing. These clinicians identified time constraints, maintenance of current genetic knowledge, and completing the consenting and counseling process as barriers to mainstreaming. Future mainstreaming models are discussed.
From the clinician's perspective, the mainstreaming program is considered a desirable pathway for germline testing of oncology patients. Access to ongoing education and resources is needed for the ongoing success of the program.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive ...renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyomadefined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.
Introduction
Mainstream genetic testing refers to genetic testing arranged by a patient's treating specialist. The aim of this study was to retrospectively review a Sydney‐based ovarian cancer ...mainstream genetic testing program.
Methods
A Cancer Genetics Service (CGS)‐supported mainstream genetic testing program was commenced in 2015. The CGS provided training, paperwork and ongoing and adaptable advice regarding appropriate genes for testing and interpretation of results. Written and electronic medical records were reviewed until August 2019 to assess patient and family history characteristics, genetic testing eligibility, results and posttest management for women who had testing coordinated via mainstreaming or by the CGS.
Results
Genetic testing was arranged for 289 women with ovarian cancer. Prior to 2017, 44% of genetic tests were mainstreamed, compared with 76% of tests from 2017 onwards. CGS was more likely to arrange testing for women with a strong family history of cancer and nonserous pathology. Germline pathogenic variants were detected in 13.7% (19/138) of women who had mainstream testing and 20.3% (14/69) of women tested by the CGS. Referral for posttest counseling occurred for pathogenic variant carriers identified through mainstreaming.
Conclusion
This study demonstrated successful uptake of a mainstream ovarian cancer genetic testing program by medical oncologists, as evidenced by higher proportion and absolute numbers of eligible ovarian cancer patients accessing genetic testing through this pathway over time. The genetic testing criteria were appropriately assessed by oncologists and posttest referral occurred where required.
Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report ...describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.
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
Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden ...of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole).
Objectives
To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above‐average risk of developing breast cancer.
Using a network meta‐analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA‐related toxicity).
Search methods
We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies.
Selection criteria
We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above‐average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events.
Data collection and analysis
Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta‐analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta‐analysis (for indirect comparisons).
Main results
We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.
For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate‐certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate‐certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high‐certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high‐certainty evidence) compared to women who received placebo.
For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high‐certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high‐certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.
For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate‐certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate‐certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.
An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data.
Authors' conclusions
For women with an above‐average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long‐term data on toxicities from tamoxifen are available while the follow‐up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk‐reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).
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