Breast Cancer Outcomes for Women Aged 18-40 Years at Diagnosis
Breast Cancer Outcomes for Women Aged 18-40 Years at Diagnosis
We present the first outcome analysis of a large prospective cohort study of young-onset breast cancer patients receiving modern breast cancer treatment. As anticipated, the major cause of death in this young trial cohort was breast cancer. The estimated five-year OS of our cohort (82%) is almost identical to 2005–2009 relative survival national statistics in 15- to 39-year-olds with breast cancer (83.5%). This confirms that the POSH cohort is representative of the wider population and that the survival of patients younger than 40 years of age at diagnosis is worse than that of patients aged 40–69 years (five-year relative survival = 89.1% to 90.4%).
Our prospective data clearly demonstrate the influence of ER status over time on recurrence risk and OS in young patients. The estimated five-year OS of patients with ER-positive tumors was 9% higher than patients with ER-negative tumors; however, by eight years the survival of young breast cancer patients with ER-positive tumors was no better than that of patients with ER-negative tumors. Whereas our data indicated falling ER-negative hazard rates and rising ER-positive hazard ratios after five years, a previous analysis of Surveillance Epidemiology and End Results (SEER) data showed falling ER-negative hazard rates and constant ER-positive rates crossing at seven years; however, this latter analysis was in non-age-selected patients. A more recent report using SEER data observed that patients younger than 40 years of age with ER-positive tumors had an increased hazard of breast cancer–specific mortality compared with that for patients with ER-negative tumors at 5–10 years after diagnosis. The increase in breast cancer–specific mortality hazard was notably less marked in older patients with ER-positive tumors. It should, however, be noted that our 10-year follow-up data are currently limited.
Notably, 10.2% of POSH patients with ER-positive tumors relapse between five and eight years (Figure 2B). Adjuvant hormone therapy is generally prescribed for a five-year period. Our results raise the question of duration of hormonal therapy in some premenopausal women. Although the National Surgical Adjuvant Breast and Bowel Project B-14 extension indicated that continuation of adjuvant tamoxifen beyond five years did not confer additional benefits, this trial was limited to node-negative patients and only 31% of patients were younger than 49 years of age. Data from the MA.17 clinical trial suggests that extended hormone therapy with letrozole may be beneficial in patients who are premenopausal at diagnosis but became amenorrheic during adjuvant treatment. This is more likely to occur in women aged 41–50 years than in those aged 40 years and younger, so further investigation is clearly required to confirm the optimum length of hormone treatment in the youngest age groups. The recently published Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) randomized trial, which included 1270 women aged 45 years or younger at diagnosis with ER-positive tumors, indicates that continuation of tamoxifen for 10 years rather than stopping at five years reduces breast cancer recurrence and mortality in both pre- and postmenopausal women.
Ovarian suppression (medical, irradiation, and/or oophorectomy) was documented in 703 of the POSH patients with ER-positive tumors. Although chemotherapy-induced amenorrhea has been associated with improved prognosis, the use of ovarian suppression in addition to chemotherapy and tamoxifen remains controversial. Our data reflect the timing of this trial prior to guidance from the National Institute for Clinical Excellence in the UK, recommending use of ovarian suppression plus chemotherapy and tamoxifen in a clinical trial setting only.
The vast majority of POSH patients (88%) with early breast cancer received chemotherapy in addition to local treatments, suggesting general compliance with the 1998 St Gallen recommendations. Most patients received anthracycline-based chemotherapy. Inevitably, standard systemic treatment regimens changed during the recruitment period of this study, including the incorporation of taxanes into adjuvant regimens. Kroman et al. reported that a diagnosis of breast cancer at a young age (particularly younger than 35 years) was a poor prognostic factor, but that the age effect was only clinically significant in patients who did not receive systemic cytotoxic therapy. However, in Kroman's series a much smaller proportion of stage 1–3 patients (65%) received chemotherapy than in POSH. Similarly, Fredholm et al. found that the excess risk in young women was most evident in women with early tumors but also reported low frequency of chemotherapy in these patients. A recent meta-analysis confirms that absolute benefits from systemic therapy are higher in patients younger than 45 years of age but that the proportional reduction in risk of relapse is largely independent of age. A more detailed exploration of the age effect is beyond the scope of this descriptive publication but will be addressed in future analyses.
Numerous previous publications have reported larger tumors in younger patients with increased nodal involvement. Our findings are consistent with these reports; there was a lower frequency of T1 tumors in our cohort than reported recently for unselected UK patients (47.7% vs 58.2%) and a larger frequency of positive lymph nodes (50.2% vs 38.4%). This may explain why the POSH cohort mastectomy rate (51%) is higher than that reported for non-age-selected symptomatic and screening-detected UK patients (43% in 2007). The upper age criterion for this trial is below the minimum age for the UK breast screening program and this trial excluded previous history of malignancy; therefore, our data do not include any examples of routine screening-detected or radiation-induced breast cancer. However, 30 patients were undergoing early screening because of a family history of breast cancer or known BRCA1/2 mutation.
Biological characteristics of tumors were consistent with other published series of women aged younger than 35 or 40 years with a high proportion of grade 3 (59%) and ER-negative (34%) tumors. Patients with an ER-negative tumor were twice as likely to have a grade 3 tumor than those with ER-positive tumors; but ER-positive tumors had a higher frequency of nodal involvement (54.0% vs 42.7% of ER-negative tumors). Although the reported frequency of HER2 overexpression was 24%, HER2 status was not routinely tested in the United Kingdom prior to 2006. Retrospective testing of primary tumors at subsequent presentation of metastatic disease would be likely to inflate the proportion of positive results among those tested. For the 1336 tumors tested on TMAs, the proportion of HER2-positive tumors was 18.2%. This is within the range reported elsewhere for all breast tumors. Overall, 19.9% of our patients were negative for HER2 overexpression, ER, and (where available) PR. Other series have described triple-negative tumors in 23%–25% of patients aged 40 years and younger.
As anticipated, a positive HER2 status is associated with a lower five-year and eight-year OS in both patients with ER-positive and those with ER-negative tumors; however, this difference is only statistically significant for patients with ER-negative tumors at eight years. Our data indicate that the eight-year OS of ER-positive/HER2-positive patients is no better than that of ER-negative/HER2-positive patients and is inferior that of to ER-positive and ER-negative patients with HER2-negative tumors. However, use of adjuvant trastuzumab was recorded for less than 50% of our cohort, which may be explained by the fact that 53.3% of the POSH cohort was diagnosed before 2005 when adjuvant trastuzumab came into routine use in the United Kingdom. It is therefore likely that these figures are not entirely representative of the modern oncological management of HER2-positive breast cancer. Most of these patients who did not receive adjuvant trastuzumab received it for metastatic disease.
POSH is a cohort study and we have therefore not directly compared our data with older women. However, we have reported according to the STROBE guidelines to ensure complete transparency in relation to our findings and future analyses. Although national registry data are incomplete, the data presented in this study appear to be comparable with national data over the same time period so are likely to be representative. One limitation of the data presented here is that ER, PR, and HER2 results were obtained from local pathology reports with variations in scoring systems. PR testing was not routinely performed at many sites during recruitment. A slightly lower proportion of our patients (2.5%) had distant metastases at presentation than in retrospective series of women younger than 35 years (3.2%) or 40 years of age (2.9%–7·0%). This may represent bias against recruitment of this group to an observational study.
As one of the few prospective studies on medium-term outcome in this age group, POSH already provides a unique data set. Further analysis from the POSH study data will provide important insights into long-term outcomes for early-onset breast cancer and the influences of genetic variation on tumor pathology and response to treatment.
We have described the presenting characteristics, pathology, and treatment of 2956 women diagnosed with breast cancer aged 40 years or younger in the United Kingdom. Despite modern oncological treatments, this group of women has a poor prognosis. Our data confirm the high frequency of ER-negative tumors in young breast cancer patients and the association of this phenotype with high tumor grade and risk of early disease recurrence. However the equally poor medium-term outcome of ER-positive tumors in this patient group, in both HER2-positive and HER2-negative subgroups, highlights the need for new treatment approaches in all younger women, including extended adjuvant hormonal therapy and possibly age-selected trials.
Discussion
We present the first outcome analysis of a large prospective cohort study of young-onset breast cancer patients receiving modern breast cancer treatment. As anticipated, the major cause of death in this young trial cohort was breast cancer. The estimated five-year OS of our cohort (82%) is almost identical to 2005–2009 relative survival national statistics in 15- to 39-year-olds with breast cancer (83.5%). This confirms that the POSH cohort is representative of the wider population and that the survival of patients younger than 40 years of age at diagnosis is worse than that of patients aged 40–69 years (five-year relative survival = 89.1% to 90.4%).
Our prospective data clearly demonstrate the influence of ER status over time on recurrence risk and OS in young patients. The estimated five-year OS of patients with ER-positive tumors was 9% higher than patients with ER-negative tumors; however, by eight years the survival of young breast cancer patients with ER-positive tumors was no better than that of patients with ER-negative tumors. Whereas our data indicated falling ER-negative hazard rates and rising ER-positive hazard ratios after five years, a previous analysis of Surveillance Epidemiology and End Results (SEER) data showed falling ER-negative hazard rates and constant ER-positive rates crossing at seven years; however, this latter analysis was in non-age-selected patients. A more recent report using SEER data observed that patients younger than 40 years of age with ER-positive tumors had an increased hazard of breast cancer–specific mortality compared with that for patients with ER-negative tumors at 5–10 years after diagnosis. The increase in breast cancer–specific mortality hazard was notably less marked in older patients with ER-positive tumors. It should, however, be noted that our 10-year follow-up data are currently limited.
Notably, 10.2% of POSH patients with ER-positive tumors relapse between five and eight years (Figure 2B). Adjuvant hormone therapy is generally prescribed for a five-year period. Our results raise the question of duration of hormonal therapy in some premenopausal women. Although the National Surgical Adjuvant Breast and Bowel Project B-14 extension indicated that continuation of adjuvant tamoxifen beyond five years did not confer additional benefits, this trial was limited to node-negative patients and only 31% of patients were younger than 49 years of age. Data from the MA.17 clinical trial suggests that extended hormone therapy with letrozole may be beneficial in patients who are premenopausal at diagnosis but became amenorrheic during adjuvant treatment. This is more likely to occur in women aged 41–50 years than in those aged 40 years and younger, so further investigation is clearly required to confirm the optimum length of hormone treatment in the youngest age groups. The recently published Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) randomized trial, which included 1270 women aged 45 years or younger at diagnosis with ER-positive tumors, indicates that continuation of tamoxifen for 10 years rather than stopping at five years reduces breast cancer recurrence and mortality in both pre- and postmenopausal women.
Ovarian suppression (medical, irradiation, and/or oophorectomy) was documented in 703 of the POSH patients with ER-positive tumors. Although chemotherapy-induced amenorrhea has been associated with improved prognosis, the use of ovarian suppression in addition to chemotherapy and tamoxifen remains controversial. Our data reflect the timing of this trial prior to guidance from the National Institute for Clinical Excellence in the UK, recommending use of ovarian suppression plus chemotherapy and tamoxifen in a clinical trial setting only.
The vast majority of POSH patients (88%) with early breast cancer received chemotherapy in addition to local treatments, suggesting general compliance with the 1998 St Gallen recommendations. Most patients received anthracycline-based chemotherapy. Inevitably, standard systemic treatment regimens changed during the recruitment period of this study, including the incorporation of taxanes into adjuvant regimens. Kroman et al. reported that a diagnosis of breast cancer at a young age (particularly younger than 35 years) was a poor prognostic factor, but that the age effect was only clinically significant in patients who did not receive systemic cytotoxic therapy. However, in Kroman's series a much smaller proportion of stage 1–3 patients (65%) received chemotherapy than in POSH. Similarly, Fredholm et al. found that the excess risk in young women was most evident in women with early tumors but also reported low frequency of chemotherapy in these patients. A recent meta-analysis confirms that absolute benefits from systemic therapy are higher in patients younger than 45 years of age but that the proportional reduction in risk of relapse is largely independent of age. A more detailed exploration of the age effect is beyond the scope of this descriptive publication but will be addressed in future analyses.
Numerous previous publications have reported larger tumors in younger patients with increased nodal involvement. Our findings are consistent with these reports; there was a lower frequency of T1 tumors in our cohort than reported recently for unselected UK patients (47.7% vs 58.2%) and a larger frequency of positive lymph nodes (50.2% vs 38.4%). This may explain why the POSH cohort mastectomy rate (51%) is higher than that reported for non-age-selected symptomatic and screening-detected UK patients (43% in 2007). The upper age criterion for this trial is below the minimum age for the UK breast screening program and this trial excluded previous history of malignancy; therefore, our data do not include any examples of routine screening-detected or radiation-induced breast cancer. However, 30 patients were undergoing early screening because of a family history of breast cancer or known BRCA1/2 mutation.
Biological characteristics of tumors were consistent with other published series of women aged younger than 35 or 40 years with a high proportion of grade 3 (59%) and ER-negative (34%) tumors. Patients with an ER-negative tumor were twice as likely to have a grade 3 tumor than those with ER-positive tumors; but ER-positive tumors had a higher frequency of nodal involvement (54.0% vs 42.7% of ER-negative tumors). Although the reported frequency of HER2 overexpression was 24%, HER2 status was not routinely tested in the United Kingdom prior to 2006. Retrospective testing of primary tumors at subsequent presentation of metastatic disease would be likely to inflate the proportion of positive results among those tested. For the 1336 tumors tested on TMAs, the proportion of HER2-positive tumors was 18.2%. This is within the range reported elsewhere for all breast tumors. Overall, 19.9% of our patients were negative for HER2 overexpression, ER, and (where available) PR. Other series have described triple-negative tumors in 23%–25% of patients aged 40 years and younger.
As anticipated, a positive HER2 status is associated with a lower five-year and eight-year OS in both patients with ER-positive and those with ER-negative tumors; however, this difference is only statistically significant for patients with ER-negative tumors at eight years. Our data indicate that the eight-year OS of ER-positive/HER2-positive patients is no better than that of ER-negative/HER2-positive patients and is inferior that of to ER-positive and ER-negative patients with HER2-negative tumors. However, use of adjuvant trastuzumab was recorded for less than 50% of our cohort, which may be explained by the fact that 53.3% of the POSH cohort was diagnosed before 2005 when adjuvant trastuzumab came into routine use in the United Kingdom. It is therefore likely that these figures are not entirely representative of the modern oncological management of HER2-positive breast cancer. Most of these patients who did not receive adjuvant trastuzumab received it for metastatic disease.
POSH is a cohort study and we have therefore not directly compared our data with older women. However, we have reported according to the STROBE guidelines to ensure complete transparency in relation to our findings and future analyses. Although national registry data are incomplete, the data presented in this study appear to be comparable with national data over the same time period so are likely to be representative. One limitation of the data presented here is that ER, PR, and HER2 results were obtained from local pathology reports with variations in scoring systems. PR testing was not routinely performed at many sites during recruitment. A slightly lower proportion of our patients (2.5%) had distant metastases at presentation than in retrospective series of women younger than 35 years (3.2%) or 40 years of age (2.9%–7·0%). This may represent bias against recruitment of this group to an observational study.
As one of the few prospective studies on medium-term outcome in this age group, POSH already provides a unique data set. Further analysis from the POSH study data will provide important insights into long-term outcomes for early-onset breast cancer and the influences of genetic variation on tumor pathology and response to treatment.
We have described the presenting characteristics, pathology, and treatment of 2956 women diagnosed with breast cancer aged 40 years or younger in the United Kingdom. Despite modern oncological treatments, this group of women has a poor prognosis. Our data confirm the high frequency of ER-negative tumors in young breast cancer patients and the association of this phenotype with high tumor grade and risk of early disease recurrence. However the equally poor medium-term outcome of ER-positive tumors in this patient group, in both HER2-positive and HER2-negative subgroups, highlights the need for new treatment approaches in all younger women, including extended adjuvant hormonal therapy and possibly age-selected trials.
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