To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen.
From a registry of 6,903 patients, we identified ...102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria.
Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin.
A low rate of pCR was observed in women with breast cancer and a BRCA1 mutation who were treated with AT or CMF. A high rate of pCR was seen after treatment with cisplatin. An intermediate rate of PCR was associated with AC or FAC. The relative benefits of AC and platinum therapy need to be confirmed through follow-up of this and other cohorts.
Neoadjuvant chemotherapy has become standard of care for cisplatin-eligible patients with muscle-invasive bladder cancer qualified to radical cystectomy, providing a modest increase in 5-year overall ...survival rate. Several regimens are being employed for neoadjuvant treatment, largely because of their efficacy in metastatic setting. There is however a scarcity of evidence on the optimal cytotoxic regimen for neoadjuvant chemotherapy.
We evaluated the efficacy of different protocols of neoadjuvant chemotherapy amongst patients who underwent radical cystectomy at our institution.
This is a single-center, retrospective, observational study including a cohort of 220 patients who underwent radical cystectomy between 2014 and 2020. The neoadjuvant chemotherapy cohort included 79 patients and was compared to the cohort of historical controls including 141 patients operated prior to routine administration of neoadjuvant chemotherapy and those who opted for upfront surgery.
Administration of neoadjuvant chemotherapy decreased the risk of overall and cancer-specific mortality HR = 0.625 (95% CI 0.414-0.944), p = 0.025 and HR = 0.579 (95% CI 0.348-0.964), p = 0.036. Rates of downstaging, complete responses, lymph node metastasis, extravesical extension and positive surgical margins significantly favored neoadjuvant chemotherapy. Out of cytotoxic regimens, dose-dense MVAC and gemcitabine-cisplatin were similarly efficacious providing 46.9% and 50% of downstaging to <ypT2N0 respectively, including 30.6% and 25% of complete remissions. However, only dose-dense MVAC was associated with reduction of all-cause and cancer specific mortality risk HR = 0.385 (95% CI 0.214-0.691) p = 0.001 and HR = 0.336 (95% CI 0.160-0.703), p = 0.004 respectively.
Our study implies that neoadjuvant chemotherapy with subsequent radical cystectomy provides significant improvement over upfront surgery in locoregional control and long-term prognosis of muscle-invasive bladder cancer. The urologic community should strive to maximize utilization of neoadjuvant chemotherapy, yet further research, including randomized control trials, is needed to validate superiority of dose-dense MVAC as the preferred regimen for cisplatin-eligible patients.
To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer.
Seven thousand four hundred ninety-four BRCA1 mutation-negative patients ...with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T).
A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio OR, 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected.
CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.
Summary Background Mutations in PALB2 predispose to breast cancer, but the effect on prognosis of carrying a PALB2 mutation has not been ascertained. We aimed to estimate the odds ratio for breast ...cancer in women with an inherited mutation in PALB2 and 10-year survival after breast cancer in patients who carry a PALB2 mutation. Methods Between 1996 and 2012, patients with invasive breast cancer were recruited prospectively from 18 hospitals in Poland and genotyped for two deleterious mutations in PALB2 (509_510delGA and 172_175delTTGT). A control group of 4702 women without cancer was recruited for comparison. The primary endpoint was death from any cause, as determined by medical records from the Polish Ministry of the Interior and Administration. In patients with breast cancer, 10-year survival of carriers of a PALB2 mutation was calculated and compared with that of non-carriers. Findings 17 900 women with breast cancer were invited to participate, of whom 12 529 were genotyped successfully. A PALB2 mutation was present in 116 (0·93%, 95% CI 0·76–1·09) of 12 529 patients and in ten (0·21%, 0·08–0·34) of 4702 controls (odds ratio 4·39, 95% CI 2·30–8·37; p<0·0001). 10-year survival for women with breast cancer and a PALB2 mutation was 48·0% (95% CI 36·5–63·2), compared with 74·7% (73·5–75·8) for patients with breast cancer without a mutation (adjusted hazard ratio for death 2·27, 95% CI 1·64–3·15; p<0·0001). Interpretation Women with a PALB2 mutation face an increased risk of breast cancer and might be at a higher risk of death from breast cancer compared with non-carriers. Increased surveillance should be offered to unaffected women who carry a PALB2 mutation. Funding Polish National Science Centre.
To estimate 10-year overall survival (OS) rates for patients with early-onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive ...breast cancer.
A total of 3,345 women with stage I to III breast cancer, age ≤ 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model.
Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75).
The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.
To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation.
We conducted a multicenter survey of 1,954 young ...women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses.
Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001).
Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation.
The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in
,
,
,
, and
genes with ovarian cancer risk among unselected patients in ...Poland. We genotyped 21 recurrent germline mutations in
(9 mutations),
(4 mutations),
(3 mutations),
(2 mutations), and
(3 mutations) among 2270 Polish ovarian cancer patients and 1743 healthy controls, and assessed the odds ratios (OR) for developing ovarian cancer for each gene. Mutations were detected in 369 out of 2095 (17.6%) unselected ovarian cancer cases and 117 out of 1743 (6.7%) unaffected controls. The ovarian cancer risk was associated with mutations in
(OR = 40.79, 95% CI: 18.67-114.78;
= 0.29 × 10
), in
(OR = 25.98; 95% CI: 1.55-434.8;
= 0.001), in
(OR = 6.28; 95% CI 1.77-39.9;
= 0.02), and in
(OR 3.34; 95% CI: 1.06-14.68;
= 0.06). There was no association found for
We found that pathogenic mutations in
,
,
or
are responsible for 12.5% of unselected cases of ovarian cancer. We recommend that all women with ovarian cancer in Poland and first-degree female relatives should be tested for this panel of 18 mutations.
Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and ...assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.
What's new?
The genetic and molecular mechanisms that lead to pancreatic cancer are still poorly understood. In this study, the authors examined founder mutations that are known to be associated with several types of cancer in Poland. They found that a particular mutation in NBS1 was associated with a significant increase in the risk of pancreatic cancer. Screening for this mutation may therefore help identify people who are at risk for pancreatic cancer in Poland and probably other Slavic populations.
There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian ...carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs.
The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated.
The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45-15.43, p=0.01).
Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required.
To investigate the contribution of a founder deletion in the CHEK2 gene to the burden of breast cancer in Poland we studied 4,454 women with breast cancer and 5,496 population controls. Cases and ...controls were genotyped for the presence of a 5,395 bp founder deletion that removes exons 9 and 10 of the CHEK2 gene. This deletion has recently been described in a Czech and Slovak population. The cases and controls had previously been tested for two protein-truncating (IVS2 + 1G > A and 1100delC) and one missense CHEK2 mutation (I157T) which are characteristic for the population. The exons 9 and 10 deletion was present in 0.4% of the controls, in 1.0% (19 of 1,978) of unselected breast cancer cases (OR=2.2; 95% CI: 1.2-4.0; p = 0.01) and in 0.9% (28 of 3,228) of the early-onset cases (OR=2.0; 95% CI: 1.3-1.8; p = 0.02). One of the three truncating CHEK2 mutations (del5395; 1100delC or IVS2 + 1G > A) was seen in 101 of 4,454 (2.3%) cases and in 58 of 5,496 controls (1.1%) (OR=2.2; 95% CI: 1.6-3.0 p < 0.0001). A 5,395 bp founder deletion contributes to the burden of breast cancer in Poland. The deletion was present in 0.9% of the women with breast cancer diagnosed under the age of 51 and in 0.9% of women with breast cancer over the age of 50. This is one of the most common protein-truncating CHEK2 variants in Poland. Overall, 2% of all breast cancers in Poland can be attributed to one of three protein-truncating mutations in CHEK2.
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