International variation in breast cancer incidence and mortality in young women.

PURPOSE: Breast cancer in young women (< 40 years) is rare and carries a poor prognosis relative to breast cancer in older women. Most studies examining global breast cancer patterns do not describe the trends in young women specifically. METHODS: Data from GLOBOCAN 2018 were used to compare breast cancer incidence and mortality rates among younger (ages 0-39) vs. older (ages 40+) women across 185 countries. The coefficient of variation (the ratio of the standard deviation to the mean) was used to quantify relative variability. RESULTS: The risk of developing breast cancer to age 39 ranged from 0.13% in Guinea to 0.95% in South Korea (coefficient of variation: 46%), and the risk of death from breast cancer to age 39 ranged from 0.02% in China to 0.72% in Cameroon (coefficient of variation: 81%). In contrast, the risk of developing breast cancer to age 74 ranged from 1.5% in Mozambique to 12.2% in Belgium (coefficient of variation: 50%), and the risk of death from breast cancer to age 74 ranged from 0.65% in South Korea to 3.0% in Somalia (coefficient of variation: 36%). CONCLUSIONS: Among young women, breast cancer mortality rates varied more worldwide than breast cancer incidence. In contrast, among older women/women of all ages, breast cancer incidence varied more than breast cancer mortality. Further research is required to examine the impact of stage at diagnosis, clinicopathologic features, and treatments received, on variations in the survival and mortality of breast cancer in young women around the world.

Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel.

BACKGROUND: The value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear. METHODS: We studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician. RESULTS: Overall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance. CONCLUSIONS: Our findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.

Predictors of time to death after distant recurrence in breast cancer patients.

BACKGROUND: After experiencing a distant recurrence, breast cancer patients have a poor prognosis; fewer than 5% survive for ten or more years. However, the time to death is highly variable, ranging from a few months to many years. The purpose of this study is to identify, in a large hospital-based series of patients with early-stage breast cancer, factors which predict survival after distant recurrence. METHODS: We studied a cohort of 2312 women diagnosed with invasive breast cancer at Women's College Hospital between 1987 and 2000 (stages I-III). For each patient, we abstracted information on age at diagnosis, the initial presentation of the cancer (tumour size, lymph node status, tumour grade, ER status, PR status, HER2 status), treatment (surgery, radiotherapy, chemotherapy, hormone therapy), the dates of all tumour recurrences (local, regional, distant) and the dates and causes of death. The Cox proportional hazards model was used to estimate the univariate and multivariate hazard ratios for death from breast cancer following distant recurrence associated with the various tumour features. RESULTS: After a mean follow-up of 12.8 years from diagnosis, 523 distant recurrences were recorded among women in the cohort (23% of 2312) and 604 women (26%) died of breast cancer. For the 484 women who had a distant recurrence on record and died of breast cancer, the mean time from distant recurrence to death was 2.0 years (range 0-11.9 years). In a multivariate analysis, only two factors were significantly associated with time to death after distant recurrence: ER status (positive vs. negative, HR 0.56; 95% CI 0.43-0.71; p < 0.0001) and tumour grade (high vs. low, HR 1.87; 95% CI 1.16-3.01; p = 0.01). Among ER-negative patients (N = 175), high tumour grade and a short time from diagnosis to distant recurrence were associated with a rapid time to death. Among ER-positive patients (N = 336), there was no significant independent predictor of time from recurrence to death. CONCLUSIONS: Among ER-negative breast cancer patients, the time to death after distant recurrence was predictable to some extent; women with a short time from diagnosis to recurrence and/or with high-grade tumours were more likely to succumb to breast cancer within 3 years. Among ER-positive breast cancer patients who experience a distant recurrence, the time to death varies substantially and between patients could not be predicted by tumour factors or treatment. This suggests that for ER-positive patients, the factors that determine the time from diagnosis to distant recurrence do not predict the course of the cancer post-recurrence.

The relationship between tumour size, nodal status and distant metastases: on the origins of breast cancer.

BACKGROUND: In patients with breast cancer, increasing tumour size at diagnosis is associated with an increased likelihood of axillary lymph node involvement and increased breast cancer-specific mortality. However, this relation is based on studies which combine all tumours smaller than 1.0 cm in a single category and all tumours larger than 5.0 cm in another category. This coarse classification may obscure a nuanced description of the effects of tumour size across the full range of possible sizes. METHODS: We examined the relationship between primary tumour size, lymph node status and distant metastases in a cohort of 819,647 women diagnosed with first primary invasive breast cancer from 1990 to 2014 in the Surveillance, Epidemiology and End Results (SEER) registries database. All patients in the cohort had a known primary tumour size between 1 and 150 mm in greatest dimension. Primary tumour size was examined as a continuous (1-150 mm) and categorical variable (15 size groups; 10-mm intervals). For each 1- or 10-mm size group, we determined the proportion of patients with positive lymph nodes at diagnosis, the proportion of patients with distant metastases at diagnosis and the actuarial cumulative risk of breast cancer-specific mortality at 15 years from diagnosis. RESULTS: Among 819,647 patients with invasive breast tumours between 1 and 150 mm in size, there was a non-linear correlation between increasing tumour size and the prevalence of lymph node metastases at diagnosis (% node-positive), the prevalence of distant metastases at diagnosis (% stage IV) and the 15-year rate of breast cancer-specific mortality across the entire size spectrum. For very small tumours (under 10 mm) and for very large tumours (larger than 60-90 mm) there was little correlation between tumour size and metastasis risk. CONCLUSIONS: The relationship between tumour size, lymph node status and distant metastases in patients with invasive breast cancer is not linear. This calls into question the conventional model that the capacity for a primary breast tumour to metastasize increases as the tumour enlarges.

Is invasion a necessary step for metastases in breast cancer?

PURPOSE: To review the empirical evidence to support the conventional (sequential) model of breast cancer progression, which is based on the paradigm that cancer passes through several stages, including an in situ stage prior to an invasive stage, and thereafter (in some cases) disseminates to the lymph nodes and distant organs. METHODS: We review the cancer literature of the last 50 years which relates to the prevention of invasive breast cancer (through radiotherapy or surgery) and reductions in the mortality for breast cancer. RESULTS: For both invasive cancers and DCIS, the literature indicates that prevention of in-breast invasive recurrences does not prevent death from breast cancer. Moreover, the presence of residual cancer cells in the breast after breast-conserving surgery does not compromise the cure rate. CONCLUSION: We propose an alternate (parallel) model of breast cancer wherein there is a small pool of cancer stem cells which have metastatic potential from their inception and which disseminate synchronously through several routes-to the breast stroma, to the lymph nodes and to distant organs. Cancer cells which disseminate to the breast give rise to cells which make up the bulk of the tumour mass but these are not the source of the distant metastases.

A comparison of two models for breast cancer mortality for women with ductal carcinoma in situ: an SEER-based analysis.

BACKGROUND: Approximately 1% of patients with ductal carcinoma in situ (DCIS) will die of breast cancer within 10 years. Women who develop an invasive breast cancer after DCIS have a much greater risk of dying than those who do not and it is often stated that these deaths are a consequence of metastases from the invasive in-breast recurrence. This progression is the result of a two-step process: first local invasive recurrence and then spread beyond the breast. A large proportion of women who die of DCIS have no record of invasive recurrence. We used SEER data and a simulation approach to test whether the actual mortality data are consistent with the two-step model. METHODS: First, we constructed Kaplan-Meier mortality curves for all patients with pure DCIS and with small node-negative invasive breast cancers in the Surveillance, Epidemiology and End Results (SEER) registries database (1998-2014). We then constructed, through simulation, theoretical breast cancer mortality curves. To model the two-step scenario, we applied the annual incidence rates of incident invasive cancer following DCIS and of death from invasive cancer after DCIS to a theoretical cohort of 100,000 women. RESULTS: The observed 15-year breast cancer-specific mortality rate for patients with pure DCIS in the SEER database was 2.0%. The expected mortality for DCIS patients (assuming a two-step process) was only 1.1% at 15 years. Assuming the mortality rates following DCIS were one-half of those observed for patients with small invasive breast cancers, the expected mortality at 15 years post-DCIS was 2.1%. CONCLUSIONS: In the SEER database, we observed far more deaths from DCIS than would be expected under a model where all deaths from breast cancer occur amongst women who experience an invasive local recurrence. This lends support to the hypothesis that DCIS mortality is not restricted to those women who experience an in-breast invasive cancer and that DCIS has properties similar to small invasive breast cancers.

Time to death in breast cancer patients as an indicator of treatment response.

PURPOSE: To describe the mortality experience of women who die of breast cancer in the 20-year period post-diagnosis using various metrics, including annual mortality rates, Kaplan-Meier survival curves and time-to-death histograms. METHODS: We generated three visual representations of SEER-based and hospital-based breast cancer patient cohorts using three different metrics of mortality. RESULTS: The greatest impact of most prognostic factors was on the probability of latent metastases present after treatment, but for some factors the primary impact was on the time to death for those women with metastases. CONCLUSIONS: The use of time-to-death statistics to display mortality benefits for treated versus untreated women helps facilitate the distinction between treatments which increase the likelihood of cure and treatments that delay cancer growth.

Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of epithelial cells which is confined within the basement membrane of the mammary ductal-lobular system. It is of interest to determine to what extent the potential to metastasize increases for DCIS patients when the basement membrane is breached (i.e. microinvasion is present). METHODS: We retrieved the records of 525,395 women who had either first primary DCIS or small (≤ 2.0 cm) node-negative invasive breast cancer in the Surveillance, Epidemiology and End Results (SEER) registries database (1990-2013). For each patient, we extracted information on year of diagnosis, age at diagnosis, tumour size, tumour grade, oestrogen receptor status, use of radiotherapy, type of surgery, cause of death and follow-up time. We classified patients into four groups, according to the size of the invasive component of the primary tumour. We estimated the actuarial rate of breast cancer-specific mortality at ten and 20 years for women in each size category. RESULTS: We identified 161,394 women with pure DCIS, 13,489 women with microinvasive carcinoma (≤ 0.1 cm of invasion), 153,856 women with invasive cancer 0.2-1.0 cm in size and 196,656 women with invasive cancer 1.1-2.0 cm in size. The 20-year actuarial breast cancer-specific mortality rate was 3.8% for women with pure DCIS, was 6.9% for women with microinvasive carcinoma, was 6.8% for women with invasive cancer 0.2-1.0 cm in size and was 12.1% for women with invasive cancer 1.1-2.0 cm in size. The adjusted hazard ratio for death associated with microinvasive carcinoma (vs. pure DCIS) was 2.00 (95% CI 1.76-2.26; p < 0.0001). CONCLUSIONS: In terms of prognosis, microinvasive cancer more closely resembles small invasive cancer 0.2-1.0 cm) than pure DCIS. For invasive cancers under 1.0 cm, size has little impact on mortality.

Predicting the presence of colon cancer in members of a health maintenance organisation by evaluating analytes from standard laboratory records.

BACKGROUND: A valid risk prediction model for colorectal cancer (CRC) could be used to identify individuals in the population who would most benefit from CRC screening. We evaluated the potential for information derived from a panel of blood tests to predict a diagnosis of CRC from 1 month to 3 years in the future. METHODS: We abstracted information on 1755 CRC cases and 54 730 matched cancer-free controls who had one or more blood tests recorded in the electronic records of Maccabi Health Services (MHS) during the period 30-180 days before diagnosis. A scoring model (CRC score) was constructed using the study subjects' blood test results. We calculated the odds ratio for being diagnosed with CRC after the date of blood draw, according to CRC score and time from blood draw. RESULTS: The odds ratio for having CRC detected within 6 months for those with a score of four or greater (vs three or less) was 7.3 (95% CI: 6.3-8.5) for men and was 7.8 (95% CI: 6.7-9.1) for women. CONCLUSIONS: Information taken from routine blood tests can be used to predict the risk of being diagnosed with CRC in the near future.

Which women decide to take tamoxifen?

PURPOSE: To identify factors which predict, among estrogen receptor (ER)-positive breast cancer patients, who chooses to take adjuvant tamoxifen. METHODS: We studied 1347 women with ER-positive breast cancer who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER status, treatments received and dates of local recurrence and of death. We compared women who did and who did not take tamoxifen for a range of factors. We used the Kaplan-Meier method to estimate 15-year local recurrence-free and breast cancer-specific survival rates for women who did and who did not take tamoxifen. RESULTS: Overall, 50.4% of women who had a mastectomy took tamoxifen and 61.0% of women who had a lumpectomy took tamoxifen (p = 0.002). Tamoxifen use did not correlate with any of the factors that were predictive of a high risk of death from breast cancer, such as young age, large tumour size and positive lymph node status. Young women (<40 years) experienced much higher mortality (41.1%) than older (>60 years) women (14.1%, p < 0.01), but were much less likely to have taken tamoxifen (35.0 vs. 74.6%, p < 0.01). CONCLUSIONS: Approximately one-half of women with ER-positive breast cancer who are candidates for tamoxifen did not take tamoxifen. Women with lumpectomy were more likely to take tamoxifen than women with mastectomy. Paradoxically, women at high risk of death from breast cancer (less than 40 at diagnosis and/or lymph node positive) and who are expected to receive the greatest benefit from tamoxifen in terms of mortality reduction were less likely to take it than were low-risk women (older women, lymph node negative). These findings suggest that women consider the reduction in risk from local recurrence to be more important than the reduction in risk of death from breast cancer when they consider taking tamoxifen.

The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients.

PURPOSE: To estimate the prognostic impact of estrogen receptor (ER)-status among women with primary invasive breast cancer, according to age at diagnosis. METHODS: We studied 1910 women with primary invasive breast cancer (stages I-III) who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER-status, treatments received (radiotherapy, chemotherapy and tamoxifen) and dates and causes of death. Patients were followed from the date of diagnosis until the date of death from breast cancer or the date of last follow-up. We used the Kaplan-Meier method to estimate the 15-year actuarial rates of breast cancer-specific survival for women with ER-positive and ER-negative breast cancer, according to age at diagnosis (categories). We used the Cox proportional hazards model to estimate the adjusted hazard ratios for death from breast cancer associated with positive ER-status (compared to negative ER-status), stratified by age at diagnosis. RESULTS: We identified 1347 women with ER-positive breast cancer (70.5%) and 563 women with ER-negative breast cancer (29.5%). Among all 1910 women in the cohort, the actuarial rate of breast cancer-specific survival at 15 years was 77% for those with ER-positive breast cancer compared to 70% for those with ER-negative breast cancer (adjusted HR = 0.69; 95% CI 0.56-0.85; p = 0.0006). The prognostic impact of ER-status differed according to age at diagnosis. Among 213 women diagnosed before age 40, breast cancer-specific survival at 15 years was worse for those with ER-positive breast cancer than for those with ER-negative breast cancer (55 vs. 61%; adjusted HR = 0.90; 95% CI 0.57-1.41; p = 0.64). In contrast, among 1697 women diagnosed between ages 40 and 75, breast cancer-specific survival at 15 years was better for those with ER-positive breast cancer than for those with ER-negative breast cancer (78 vs. 72%; adjusted HR = 0.60; 95% CI 0.47-0.76; p < 0.0001). CONCLUSIONS: Positive ER-status is a favourable prognostic factor among women diagnosed with breast cancer at or above age 40, but not among women diagnosed before age 40.

Impact of a prior diagnosis of DCIS on survival from invasive breast cancer.

A diagnosis of invasive breast cancer after DCIS can be described as a new primary cancer or as a local invasive recurrence. It is of interest to determine if, among women with early-stage breast cancer, a past history of DCIS influences survival. We retrieved the records of 306,249 women diagnosed with stage I or stage II breast cancer between 2004 and 2012, in the surveillance, epidemiology, and end results registries database, of whom 5395 had a previous diagnosis of DCIS. For each patient, we extracted information on the year of diagnosis, age at diagnosis, tumor size, nodal status, grade, estrogen receptor status, type of surgery (lumpectomy/mastectomy), use of radiotherapy (no/yes), prior DCIS (no/yes), cause of death, and follow-up time. For each case with prior DCIS, we recorded information on the year of diagnosis of DCIS, laterality of DCIS, and treatments received for DCIS. We matched 3979 patients with a prior DCIS to 3979 patients without a prior DCIS, according to the various prognostic features of the invasive cancer. We estimated the risk of death from breast cancer for patients with invasive ductal carcinoma, with and without a prior diagnosis of DCIS. We identified 306,249 women with stage I/II breast cancer, of whom 2335 had a prior ipsilateral DCIS and 3060 had a prior contralateral DCIS. Breast cancer-specific survival at 9 years was 94.6 % for patients with a prior DCIS (ipsilateral or contralateral) and was 95.2 % for patients with no prior DCIS (p = 0.32). In a matched analysis (3979 matched pairs), the hazard ratio for death from breast cancer for patients with a prior ipsilateral DCIS, compared to patients with no prior DCIS, was 0.91 (95 % CI = 0.49-1.68; p = 0.75). A prior diagnosis of ipsilateral DCIS does not impact upon the prognosis of women with early-stage invasive breast cancer. This suggests that primary breast cancers and local invasive recurrences following DCIS are similar conditions and should be treated in the same way.

The relationship between local recurrence and death in early-stage breast cancer.

To examine the relationship between local recurrence and breast cancer mortality in women with early-stage breast cancer. We studied 1675 women with stage 0 (DCIS), stage I or stage II breast cancer who were treated with breast-conserving surgery at Women's College Hospital between 1987 and 2009. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, tumour grade, lymphovascular invasion, oestrogen receptor status, progesterone receptor status, HER2 status and treatments received (radiotherapy, chemotherapy and tamoxifen). Patients were followed from the date of diagnosis until local recurrence, death from breast cancer or the date of last follow-up. We used the Kaplan-Meier method to estimate 15-year local recurrence-free and breast cancer-specific survival rates for each stage at diagnosis. For each stage, the two rates were compared. After a mean follow-up of 13.1 years, 243 women (14.5 %) experienced a local recurrence and 281 women (16.8 %) died of breast cancer. The 15-year actuarial rate of local recurrence was 16 % for women with DCIS, 15 % for women with stage I cancer and 16 % for women with stage II cancer. The 15-year breast cancer-specific mortality rate was 3 % for women with DCIS, 10 % for women with stage I breast cancer and 30 % for women with stage II breast cancer. After experiencing a local recurrence, the 15-year breast cancer mortality rate was 16 % for women with DCIS, 32 % for women with stage I breast cancer and 59 % for women with stage II breast cancer. Across the spectrum of the early stages of breast cancer, the risk of local recurrence does not correlate with the risk of death from breast cancer. After local recurrence, the risk of death from breast cancer depends on the initial stage at diagnosis.

Ten-year survival in women with primary stage IV breast cancer.

PURPOSE: To evaluate breast cancer-specific survival at 10 years in patients who present with primary stage IV breast cancer, and to determine whether survival varies with age of diagnosis. METHODS: We retrieved the records of 25,323 women diagnosed with primary stage IV breast cancer in the surveillance, epidemiology, and end results 18 registries database from 1990 to 2012. For each case, we extracted information on age at diagnosis, tumour size, nodal status, oestrogen receptor status, progesterone receptor status, ethnicity, cause of death and date of death. The Cox proportional hazards model was used to estimate the unadjusted and adjusted hazard ratio (HR) of death due to stage IV breast cancer, according to age group. RESULTS: Among 25,323 women with stage IV breast cancer, 2542 (10.0 %) were diagnosed at age 40 or below, 5562 (22.0 %) were diagnosed between ages 41 and 50 and 17,219 (68.0 %) were diagnosed between ages 51 and 70. After a mean follow-up of 2.2 years, 16,387 (64.7 %) women died of breast cancer (median survival 2.3 years). The ten-year actuarial breast cancer-specific survival rate was 15.7 % for women ages 40 and below, 14.9 % for women ages 41-50 and 11.7 % for women ages 51 to 70 (p < 0.0001). In an adjusted analysis, the risk of death from breast cancer at 10 years was significantly lower for women ages 40 and below (HR 0.78; 95 % CI 0.74-0.82; p < 0.0001) and for women ages 41-50 (HR 0.82; 95 % CI 0.79-0.85; p < 0.0001), compared to women ages 51-70. CONCLUSIONS: Approximately 13 % of women with primary stage IV breast cancer survive 10 years after diagnosis. Women diagnosed with stage IV breast cancer before age 50 have better survival at 10 years compared to older women.

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.

Low-grade serous ovarian cancer: A review.

Epithelial ovarian cancers can be divided into the more common, aggressive type II cancers and the less common, slow-growing type I cancers. Under this model, serous ovarian carcinomas can be subdivided into high-grade (type II) and low-grade (type I) tumours. The two-tier system for grading serous ovarian carcinomas is superior to more detailed grading systems in terms of predicting survival. Low-grade serous carcinomas typically present in young women and have a relatively good prognosis, despite being resistant to chemotherapy. Low-grade serous cancers have a high prevalence of KRAS and BRAF mutations, but a low prevalence of TP53 mutations (which are characteristic of high-grade serous cancers). Among women with low-grade serous ovarian cancer, the presence of a KRAS/BRAF mutation is a favorable prognostic factor. Studies of the mitogen-activated protein kinase (MAPK) inhibitor in low-grade serous ovarian cancer suggest that identifying MAPK mutations might eventually be useful in guiding treatment.

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.

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.