Victoria Sopik

Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma In Situ

IMPORTANCE Women with ductal carcinoma in situ (DCIS), or stage 0 breast cancer, often experience a second primary breast cancer (DCIS or invasive), and some ultimately die of breast cancer. OBJECTIVE To estimate the 10- and 20-year mortality from breast cancer following a diagnosis of DCIS and to establish whether the mortality rate is influenced by age at diagnosis, ethnicity, and initial treatment received. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who received a diagnosis of DCIS from 1988 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Age at diagnosis, race/ethnicity, pathologic features, date of second primary breast cancer, cause of death, and survival were abstracted for 108,196 women. Their risk of dying of breast cancer was compared with that of women in the general population. Cox proportional hazards analysis was performed to estimate the hazard ratio (HR) for death from DCIS by age at diagnosis, clinical features, ethnicity, and treatment. MAIN OUTCOMES AND MEASURES Ten- and 20-year breast cancer-specific mortality. RESULTS Among the 108 196 women with DCIS, the mean (range) age at diagnosis of DCIS was 53.8 (15-69) years and the mean (range) duration of follow-up was 7.5 (0-23.9) years. At 20 years, the breast cancer-specific mortality was 3.3% (95% CI, 3.0%-3.6%) overall and was higher for women who received a diagnosis before age 35 years compared with older women (7.8% vs 3.2%; HR, 2.58 [95% CI, 1.85-3.60]; P < .001) and for blacks compared with non-Hispanic whites (7.0% vs 3.0%; HR, 2.55 [95% CI, 2.17-3.01]; P < .001). The risk of dying of breast cancer increased after experience of an ipsilateral invasive breast cancer (HR, 18.1 [95% CI, 14.0-23.6]; P < .001). A total of 517 patients died of breast cancer following a DCIS diagnosis (mean follow-up, 7.5 [range, 0-23.9] years) without experiencing an in-breast invasive cancer prior to death. Among patients who received lumpectomy, radiotherapy was associated with a reduction in the risk of ipsilateral invasive recurrence at 10 years (2.5% vs 4.9%; adjusted HR, 0.47 [95% CI, 0.42-0.53]; P < .001) but not of breast cancer-specific mortality at 10 years (0.8% vs 0.9%; HR, 0.86 [95% CI, 0.67-1.10]; P = .22). CONCLUSIONS AND RELEVANCE Important risk factors for death from breast cancer following a DCIS diagnosis include age at diagnosis and black ethnicity. The risk of death increases after a diagnosis of an ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years.

Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis

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.

Why have ovarian cancer mortality rates declined? Part I. Incidence

The age-adjusted mortality rate from ovarian cancer in the United States has declined over the past several decades. The decline in mortality might be the consequence of a reduced number of cases (incidence) or a reduction in the proportion of patients who die from their cancer (case-fatality). In part I of this three-part series, we examine rates of ovarian cancer incidence and mortality from the Surveillance Epidemiology and End Results (SEER) registry database and we explore to what extent the observed decline in mortality can be explained by a downward shift in the stage distribution of ovarian cancer (i.e. due to early detection) or by fewer cases of ovarian cancer (i.e. due to a change in risk factors). The proportion of localized ovarian cancers did not increase, suggesting that a stage-shift did not contribute to the decline in mortality. The observed decline in mortality paralleled a decline in incidence. The trends in ovarian cancer incidence coincided with temporal changes in the exposure of women from different birth cohorts to various reproductive risk factors, in particular, to changes in the use of the oral contraceptive pill and to declining parity. Based on recent changes in risk factor propensity, we predict that the trend of the declining age-adjusted incidence rate of ovarian cancer in the United States will reverse and rates will increase in coming years.

BRCA1 and BRCA2 mutations and the risk for colorectal cancer

Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high‐risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2–9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early‐onset colorectal cancer, and offered colonoscopy at 3‐ to 5‐year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter.

Genetic risk assessment and prevention: the role of genetic testing panels in breast cancer

Multigene panel tests are being increasingly used for the genetic assessment of women with an apparent predisposition to breast cancer. Here, we review all studies reporting results from individuals who have undergone multigene panel testing for hereditary breast cancer. Across all gene panel studies, the prevalence of pathogenic mutations was highest in BRCA1 (5.3%) and BRCA2 (3.6%) and was lowest in PTEN (0.1%), CDH1 (0.1%) and STK11 (0.01%). After BRCA1/2, the prevalence of pathogenic mutations was highest in CHEK2 (1.3%), PALB2 (0.9%) and ATM (0.8%). The prevalence of variants of unknown significance was highest in ATM (9.6%). Based on the prevalence and penetrance of pathogenic mutations and the prevalence of variants of unknown significance, it is our interpretation that BRCA1, BRCA2, PALB2 and CHEK2 are the best candidates for inclusion in a clinical multigene breast cancer panel.

Why have ovarian cancer mortality rates declined? Part II. Case-fatality

In the United States, the age-adjusted mortality rate from ovarian cancer declined by 8% from 1975 to 1991 and by 18% from 1992 to 2011. A decline in the incidence rate of ovarian cancer paralleled the decline in mortality (described in Part I). The decline in mortality might also be due to a reduced proportion of ovarian cancer patients who die from their cancer (case-fatality). Here, we examine rates of ovarian cancer case-fatality from the Surveillance Epidemiology and End Results (SEER) registry database, and we consider to what extent advances in treatment also contribute to the observed decline in mortality. From 1973 to 1999, the five-year case-fatality rate for women with ovarian cancer fell by 7.5%, whereas the 12-year case-fatality rate fell by only 1.2%. The declines in five-year case-fatality corresponded in time with the introduction and expansion in use of cis-platinum and paclitaxel in clinical practice. However, modest declines in 12-year case-fatality indicate that the introduction of chemotherapy has not contributed to the decline in mortality. Developments in the last two decades include targeted therapies, aggressive surgical techniques, the use of neoadjuvant chemotherapy and intraperitoneal chemotherapy. The impact of these treatment modalities on ovarian cancer mortality still needs to be evaluated.

Genetic testing for RAD51C mutations: in the clinic and community

Much of the observed familial clustering of breast and ovarian cancer cannot be explained by mutations in BRCA1 and BRCA2. Several other cancer susceptibility genes have been identified, but their value in routine clinical genetic testing is still unclear. Germline mutations in RAD51C have been identified in about 1% of hereditary breast and ovarian cancer families. RAD51C mutations are predominantly found in families with a history of ovarian cancer and are rare in families with a history of breast cancer alone. RAD51C is primarily an ovarian cancer susceptibility gene. A mutation is present in approximately 1% of unselected ovarian cancers. Among mutation carriers, the lifetime risk of ovarian cancer is approximately 9%. The average age at onset is approximately 60 years; this suggests that preventive oophorectomy can be delayed until after natural menopause. Under current guidelines, genetic testing for RAD51C is expected to have a limited impact on ovarian cancer incidence at a population level. This is because the penetrance is 9% to age 80; the great majority of families with mutations would be represented by a single case of ovarian cancer, these are potentially preventable through population screening but not through screening of established ovarian cancer families.

Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.

A number of genes other than BRCA1 and BRCA2 have been associated with breast cancer predisposition, and extended genetic testing panels have been proposed. It is of interest to establish the full spectrum of deleterious mutations in women with familial breast cancer.We performed whole‐exome sequencing of 144 women with familial breast cancer and negative for 11 Polish founder mutations in BRCA1, CHEK2 and NBS1, and we evaluated the sequences of 12 known breast cancer susceptibility genes. A truncating mutation in a breast cancer gene was detected in 24 of 144 women (17%) with familial breast cancer. A BRCA2 mutation was detected in 12 cases, a (non‐founder) BRCA1 mutation was detected in 5 cases, a PALB2 mutation was detected in 4 cases and an ATM mutation was detected in 2 cases. Polish women with familial breast cancer who are negative for founder mutations in BRCA1, CHEK2 and NBS1 should be fully screened for mutations in BRCA1, BRCA2 and PALB2. The PALB2 founder mutation c.509_519delGA should be included in the panel of Polish founder mutations.

Why have ovarian cancer mortality rates declined? Part III. Prospects for the future

Over the last 40 years, the age-adjusted ovarian cancer mortality rate in the USA declined by 23%. The decline in mortality paralleled a decline in incidence, which was largely due to changes in reproductive risk factors. There was no reduction in ovarian cancer case-fatality at 12 years, indicating that improvements in early detection or in treatment did not contribute to the decline in mortality. Here, we discuss potential strategies to further reduce ovarian cancer mortality through prevention, early detection and treatment. The first approach is to increase genetic testing, in order to identify women who are at a high risk of developing ovarian cancer and offer them preventive bilateral salpingo-oophorectomy. At present, up to 17% of ovarian cancers are potentially preventable through population-based genetic testing of known ovarian cancer susceptibility genes. The second approach is to increase the proportion of ovarian cancer patients who achieve a status of no residual disease through primary debulking surgery and subsequently receive adjuvant intraperitoneal chemotherapy. We believe that through a combination of screening to better identify low-volume advanced stage ovarian cancer, aggressive surgery to leave no residual disease and adjuvant intraperitoneal chemotherapy, the cure rate of ovarian cancer might be improved significantly.

A model for ovarian cancer progression based on inherent resistance.

OBJECTIVE Women with ovarian cancer are treated with debulking surgery and chemotherapy. The bulk of ovarian cancer cells are resistant to chemotherapy prior to the death of the patient. It is not clear if chemoresistance is an acquired property of cells under the selective pressure of chemotherapy or if it is an innate property of a small proportion of cancer cells from the outset. METHODS We developed a mathematical model to describe ovarian cancer progression based on the assumption that a small proportion of ovarian cancer cells are chemoresistant from the beginning (0.1%) and that there is no acquired resistance. The doubling time was fixed at two months for sensitive cells and four months for resistant cells. RESULTS The proportion of chemoresistant cells increased over time and at the time of death, 90% of cells were resistant. The typical patient responded to the first three rounds of chemotherapy but was non-responsive thereafter. When we assume that the doubling times of the cancer cells is not fixed, but varies according to a normal distribution, the mean doubling time of the cells diminishes with time from diagnosis and death ensues shortly after chemoresistance is observed. CONCLUSIONS We show that a model of inherent resistance in ovarian cancer is able to recapitulate the clinical history of a typical patient with ovarian cancer and that it is not necessary to invoke acquired resistance. This observation has potential clinical implications about how to approach new therapies.