Abstract
Background
There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50.
Methods
Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36–50 years patients.
Results
Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN + macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS [HR 1.56, 95% CI 1.32–1.84; p < 0.001], and OS [HR 1.29, 95% CI 1.03–1.60; p = 0.025], as were high grade, large tumor, LVI, pN + macro, ER-negativity, period of diagnostic, and absence of ET or CT (for DFS). Adverse prognostic impact of age ≤35 was maintained in the case control-matched analysis for DFS [HR 1.56, 95%CI 1.28–1.91, p < 0.001], and OS [HR 1.33, 95%CI 1.02–1.73, p = 0.032]. When only considering patients ≤35, ER, tumor size, nodal status, and LVI were independently associated with survival in this subgroup.
Conclusions
Age ≤35 is associated with less favorable presentation and more aggressive treatment strategies. Our results support the poor prognosis value of young age, which independently persisted when adjusting for other prognostic factors and treatments.
Keywords: Early breast cancer, Very young patient, Under 35 years old, Prognostic of young age, Impact of age, Young breast cancer
Abbreviations: BC, Breast Cancer; SLNB, Sentinel Lymph Node Biopsy; ALND, Axillary Lymph Node Dissection; SBR grade, Scarff-Bloom-Richardson grade; ER, endocrine receptors; HER2, Human Epidermal growth factor Receptor 2; LVI, lymphovascular invasion; luminal-A, (HER2 negative, ER positive, SBR grade 1 or 2); luminal-B, HER2-negative, (HER2 negative, ER positive, SBR grade 3); luminal-B, HER2-positive, (HER2 positive, ER positive, all grades); HER2-positive, (non-luminal, HER2 positive, ER negative); triple-negative, (basal like, HER2 negative, ER negative); ER+, positive endocrine receptor; ER-, negative endocrine receptor; HER2+, HER2 positive; HER2-, HER2 negative; pN0, no invasion; pN0i+, isolated tumor cells; pN + mi, microscopic invasion under 2 mm; pN + macro, macroscopic invasion beyond; CT, chemotherapy; RT, radiation therapy; ET, endocrine therapy; DFS, Disease Free Survival; OS, Overall Survival; HR, Hazard Ratio; 95%CI, confidence interval at 95%; ER-, Endocrine Receptor Negative; ER+, Endocrine Receptor Positive; LumA, Luminal-A subtype; LumB G3, Luminal-B HER2-negative SBR grade 3 subtype; LumB HER2+, Luminal-B HER2-positive subtype; HER2+, HER2-positive subtype; TN, Triple-Negative subtype
Highlights
-
•
Young age is an independent prognostic factor.
-
•
Age ≤35 is associated with more severe presentation and more aggressive treatments.
-
•
Triple-negative, HER2-positive, and luminal-B subtypes are more common.
1. Introduction
Breast cancer (BC) incidence increases with age. However, one in forty patients will be diagnosed under the age of 35, thereby making it the leading cancer in young women [1,2]. Technological and therapeutic advances have led to a significant decrease in overall mortality over time, but when examined by age groups, it appears that cancer-related death in premenopausal patients tends to remain relatively stable over time. The association between young age and prognosis has been recognized for a long time [[3], [4], [5]] but its independent value is still debated [6]. According to European recommendations, treatment decisions in young women should not be motivated by their age but rather by BC presentation, to avoid overtreatment [7,8]. These recommendations assume that prognostic factors that are recognized in older women are equally valid and robust in younger women. We decided to focus on women under 35 years to try to answer three questions: what is the presentation of BC in patients ≤35 years compared to older pre-menopausal patients? Is young age by itself an independent prognostic factor? And are the prognostic factors classically identified in BC also evident in this population? To this end, we compared patients ≤35 years with a group of patients aged 36 to 50 extracted from a large retrospective multi-institutional cohort.
2. Methods
Our data were extracted retrospectively from a multicentric database comprising 23,134 patients who underwent primary surgery for early BC, from 15 French centers between 1990 and 2014. Data concerning relapse and vital status of patients were updated annually (last update May 7, 2021). Patients were included based on histologically proven invasive BC, with sentinel lymph node biopsy (SLNB) evaluation ± axillary lymph node dissection (ALND). Patients aged ≤50 were selected and divided into two groups: patients aged ≤35 years as the population of interest and patients aged 36 to 50 as a control group of premenopausal patients. We analyzed diagnostic period, tumor size, histological type, SBR grade, endocrine receptors (ER; positivity threshold 10%), Human Epidermal growth factor Receptor 2 (HER2) status, molecular subtypes determined by immunohistochemistry, SLNB or ALND, final lymph node status, and lymphovascular invasion (LVI) [9]. Five molecular subtypes were defined: luminal-A {HER2 negative (HER2-), ER-positive (ER+), grade 1 or 2}; luminal-B HER2-negative {HER2-, ER+, grade 3}; luminal-B HER2-positive {HER2 positive (HER2+), ER+, all grade}; HER2-positive {HER2+, ER-negative (ER-)}; triple-negative {basal like, HER2-, ER-}. Final lymph node status was categorized into four groups: no invasion (pN0), isolated tumor cells (pN0i+), microscopic invasion <2 mm (pN + micro), and macroscopic invasion beyond (pN + macro) [10]. Treatments, including surgery type, chemotherapy (CT), radiation therapy (RT), and endocrine therapy (ET) were analyzed. The database did not include any mutational data, thus BRCA mutation status was not known. Disease Free Survival (DFS), defined as the time from surgery to the first event (invasive relapse, metastatic relapse, or death from any cause), and Overall Survival (OS), defined as the time from surgery to death, were analyzed. Patients with missing data on evaluated variables were removed from multivariate analysis. All procedures involving human participants were done according to the French ethical standards and the Helsinki declaration. Authorization to use the database was obtained from the strategic orientation committee of Paoli-Calmettes Institute (ClinicalTrials.gov NCT02869607).
Standard descriptive statistics were used to describe patient and tumor characteristics. Deaths with no evidence of recurrence were treated as competing events in cumulative incidence analyses. Factors associated with DFS, and OS were determined in univariate and multivariate analysis. Survivals were estimated using the Kaplan-Meier method and compared with log-rank test. Multivariate Cox analyses were built for the total cohort and specifically for the ≤35 years old cohort. The hazard ratio (HR) was determined with a 95% confidence interval [95%CI]. Significance level was set at 0.05. To further assess the independent impact of age on survivals, a 1 to 3 case-control analysis was performed by matching ≤35 to 36–50 years old patients. Coefficients of a logistic regression adjusted on histology, grade, tumor size, LVI, nodal status, ER, ET, and CT were used to compute a propensity score for each patient. Each pair (1–3) were comparable on these criteria, but distinct by age. Patients not meeting all the matching criteria were excluded. Nearest-neighbor 1:3 matching without replacement was performed with a caliper of 0.2 [[11], [12], [13]]. All statistical tests were two-sided. Statistical analyses were performed with SPSS-16.0 (SPSS Inc., Chicago, Illinois, USA) and R version-3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).
3. Results
3.1. BC presentation in patients ≤35 years compared to 36–50 patients
From the 23,134 patients, a cohort of 6481 patients aged ≤50 years was extracted. Among them, 556 were aged ≤35 years and 5925 from 36 to 50 (Table 1 and Fig. 1).
Table 1.
Histopathological characteristics and treatments of the two populations: ≤35 and 36–50 years old.
| UNIVARIATE |
Total |
≤35 y (n = 556) |
36-50 y (n = 5925) |
p value |
|||||
|---|---|---|---|---|---|---|---|---|---|
| Characteristics | n | total | n | % | total | n | % | ||
| Period | 6481 | 556 | 5925 | 0.037 | |||||
| Before 2005 | 334 | 60% | 3287 | 56% | |||||
| After 2005 | 222 | 40% | 2638 | 45% | |||||
| Tumor size | 6392 | 542 | 5850 | <0.001 | |||||
| ≤5 mm | 38 | 7% | 397 | 7% | |||||
| 6–10 mm | 83 | 15% | 1305 | 22% | |||||
| 11–20 mm | 230 | 42% | 2525 | 43% | |||||
| >20 mm | 191 | 35% | 1623 | 28% | |||||
| Histological type | 6100 | 527 | 5573 | <0.001 | |||||
| Ductal | 493 | 94% | 4775 | 86% | |||||
| Lobular | 28 | 5% | 665 | 12% | |||||
| Mixed | 6 | 1% | 133 | 2% | |||||
| SBR grade | 6262 | 527 | 5735 | <0.001 | |||||
| Grade 1 | 60 | 11% | 1733 | 30% | |||||
| Grade 2 | 240 | 46% | 2675 | 47% | |||||
| Grade 3 | 227 | 43% | 1327 | 23% | |||||
| ER | 6481 | 556 | 5925 | <0.001 | |||||
| Negative | 211 | 38% | 1141 | 19% | |||||
| Positive | 345 | 62% | 4784 | 81% | |||||
| Estrogen receptor | 5839 | 478 | 5361 | <0.001 | |||||
| Negative | 180 | 38% | 1003 | 19% | |||||
| Positive | 298 | 62% | 4358 | 81% | |||||
| Progesterone receptor | 5527 | 467 | 5060 | <0.001 | |||||
| Negative | 185 | 40% | 1217 | 24% | |||||
| Positive | 282 | 60% | 3843 | 76% | |||||
| HER2 overexpressed | 6481 | 556 | 5925 | <0.001 | |||||
| No | 252 | 45% | 3334 | 56% | |||||
| Yes | 77 | 14% | 433 | 7% | |||||
| Unknown | 227 | 41% | 2158 | 36% | |||||
| Molecular subtype | 4425 | 329 | 4096 | <0.001 | |||||
| Luminal A | 139 | 42% | 2724 | 67% | |||||
| HER2+ | 31 | 9% | 160 | 4% | |||||
| Triple negative | 61 | 19% | 434 | 11% | |||||
| Luminal B G3 | 52 | 16% | 428 | 10% | |||||
| Luminal B HER2+ | 46 | 14% | 350 | 9% | |||||
| SLNB and/or ALND | 6470 | 554 | 5916 | <0.001 | |||||
| SLNB | 155 | 28% | 2376 | 40% | |||||
| SLNB + ALND | 152 | 27% | 1768 | 30% | |||||
| ALND | 247 | 45% | 1772 | 30% | |||||
| Final lymph node status | 6447 | 549 | 5898 | <0.001 | |||||
| pN0 | 275 | 50% | 3489 | 59% | |||||
| pN0(i+) | 23 | 4% | 166 | 3% | |||||
| pN + mi | 35 | 6% | 474 | 8% | |||||
| pN + macro | 216 | 39% | 1769 | 30% | |||||
| LVI | 5599 | 491 | 5108 | <0.001 | |||||
| No | 244 | 50% | 3495 | 68% | |||||
| Yes | 247 | 50% | 1613 | 32% | |||||
| Surgery type | 6481 | 548 | 5835 | <0.001 | |||||
| Lumpectomy | 377 | 69% | 4516 | 77% | |||||
| Mastectomy | 171 | 31% | 1319 | 23% | |||||
| Adjuvante CT | 6481 | 556 | 5925 | <0.001 | |||||
| No | 93 | 17% | 2617 | 44% | |||||
| Yes | 441 | 79% | 3215 | 54% | |||||
| Neo-adjuvant | 22 | 4% | 93 | 2% | |||||
| Trastuzumab | 6137 | 536 | 5601 | <0.001 | |||||
| No | 479 | 89% | 5334 | 95% | |||||
| Yes | 57 | 11% | 267 | 5% | |||||
| RT | 6192 | 539 | 5653 | 0.352 | |||||
| No | 40 | 7% | 423 | 7% | |||||
| Yes | 499 | 93% | 5230 | 93% | |||||
| ET | 6476 | 556 | 5920 | <0.001 | |||||
| No | 242 | 44% | 1714 | 29% | |||||
| Yes | 314 | 56% | 4206 | 71% | |||||
| Relapse | 6480 | 556 | 5924 | <0.001 | |||||
| No | 369 | 66% | 4996 | 84% | |||||
| Yes | 187 | 34% | 928 | 16% | |||||
| Relapse type | 1116 | 187 | 929 | 0.253 | |||||
| Axillary | 6 | 3% | 39 | 4% | |||||
| Metastatic | 120 | 64% | 516 | 56% | |||||
| Others | 38 | 20% | 235 | 25% | |||||
| Controlateral | 16 | 9% | 84 | 9% | |||||
| Unspecified | 7 | 4% | 55 | 6% | |||||
Fig. 1.
Flow chart of the population.
Compared to the 36–50 years old group, patients ≤35 had significantly larger tumor (35% above 20 mm in ≤35 versus 28% in 36–50), grade 3 (43% versus 23%), pN + macro (39% versus 30%), and LVI (50% versus 32%). Patients ≤35 had more ER-tumors (23% versus 11%), and HER2+ (14% versus 7%). Molecular subtypes distribution was different according to age group (p < 0.001): luminal-A tumors were principally represented in the 36–50 patients (67% versus 42% of ≤35), while ≤35 patients presented more triple-negative (19% versus 11%), luminal-B HER2-negative (16% versus 10%), luminal-B HER2-positive (14% versus 9%), and HER2-positive (9% versus 4%) tumors (Fig. 1). Lobular subtype was more frequent in 36–50 years old patients (12% versus 5%). Age ≤35 years was significantly associated with increased rates of mastectomy (31% versus 23%), adjuvant CT (79% versus 54%), neo-adjuvant CT (4% versus 2%), and ALND (45% versus 30%). No difference was observed for RT or ET use among ER + patients (Table 1).
3.2. Prognostic value of age ≤35 - Univariate survival analysis
With a median follow-up of 71.9 months [95%CI 70.7–73.1], DFS events occurred in 34% of ≤35 patients versus 16% of 36–50 (p < 0.001). However, no difference was observed by type of relapse (Table 1).
In univariate analysis, patients ≤35 presented lower 5- and 10-year DFS than the 36–50 cohort: 74% [95%CI 70.88–78.12] versus 89% [95%IC 87.89–89.51]; p < 0.001, and 60% [95%IC 55.52–63.68] versus 74% [95%IC 73.29–75.51]; p < 0.001, respectively (Fig. 2). HR for continuous DFS was unfavorable for ≤35 women [1.90, 95%CI 1.63–2.33, p < 0.001] (Table 2, Fig. 3). OS events were more frequent in the ≤35 group (19%) than in the 36–50 (9%) (p < 0.001). In univariate analysis, patients ≤35 presented lower 5- and 10-year OS than 36–50: 89% [95%IC 86.84–91.96] versus 95% [95%IC 94.76–95.84]; p < 0.001, and 76% [95%IC 72.76–79.83] versus 86% [95%IC 84.81–86.59]; p < 0.001, respectively (Fig. 2). HR for continuous OS was unfavorable for ≤35 [1.76, 95%CI 1.43–2.17, p < 0.001] (Table 2, Fig. 3).
Fig. 2.
Kaplan Meier of univariate analysis of DFS (A) and OS (B) in both cohorts.
Table 2.
Multivariate analysis of DFS and OS in the total cohort.
| TOTAL |
DFS |
OS |
||||||
|---|---|---|---|---|---|---|---|---|
| COHORT |
HR |
95% CI |
p value |
HR |
95% CI |
p value |
||
| min | max | min | max | |||||
| Age | 1.56 | 1.32 | 1.84 | <0.001 | 1.29 | 1.03 | 1.60 | 0.025 |
| CT | ||||||||
| No | Reference category | Reference category | ||||||
| Adjuvant | 0.83 | 0.70 | 0.99 | 0.035 | 0.86 | 0.67 | 1.10 | 0.218 |
| Neo-adjuvant | 1.26 | 0.79 | 2.02 | 0.326 | 1.51 | 0.78 | 2.92 | 0.221 |
| ER | 0.89 | 0.73 | 1.08 | 0.239 | 0.72 | 0.56 | 0.92 | 0.010 |
| ET | 0.73 | 0.60 | 0.88 | 0.001 | 0.82 | 0.64 | 1.07 | 0.141 |
| SBR grade | ||||||||
| 1 | Reference category | Reference category | ||||||
| 2 | 1.37 | 1.15 | 1.63 | <0.001 | 1.53 | 1.16 | 2.01 | 0.003 |
| 3 | 1.64 | 1.35 | 2.00 | <0.001 | 2.33 | 1.74 | 3.13 | <0.001 |
| Size (mm) | ||||||||
| ≤5 | Reference category | Reference category | ||||||
| 5 to 10 | 0.77 | 0.56 | 1.06 | 0.107 | 0.56 | 0.33 | 0.94 | 0.027 |
| 10 to 20 | 0.90 | 0.66 | 1.22 | 0.484 | 0.84 | 0.52 | 1.36 | 0.477 |
| 20 to 50 | 1.12 | 0.82 | 1.52 | 0.482 | 1.26 | 0.79 | 2.03 | 0.333 |
| >50 | 2.21 | 1.54 | 3.17 | <0.001 | 2.40 | 1.41 | 4.06 | 0.001 |
| Lymph node involvement | ||||||||
| pN0 | Reference category | Reference category | ||||||
| pN0(i+) | 1.03 | 0.67 | 1.57 | 0.902 | 0.87 | 0.41 | 1.87 | 0.722 |
| pN1mi | 0.86 | 0.63 | 1.18 | 0.347 | 1.02 | 0.62 | 1.68 | 0.941 |
| pN1macro | 1.37 | 1.17 | 1.60 | <0.001 | 1.67 | 1.34 | 2.08 | <0.001 |
| LVI | ||||||||
| No | Reference category | Reference category | ||||||
| Yes | 1.36 | 1.18 | 1.57 | <0.001 | 1.67 | 1.37 | 2.03 | <0.001 |
| Unknown | 1.06 | 0.88 | 1.28 | 0.543 | 1.21 | 0.92 | 1.58 | 0.170 |
| Histological type | ||||||||
| Ductal | Reference category | Reference category | ||||||
| Lobular | 0.90 | 0.72 | 1.12 | 0.336 | 0.94 | 0.68 | 1.29 | 0.688 |
| Mixed | 0.73 | 0.47 | 1.13 | 0.160 | 0.94 | 0.54 | 1.64 | 0.817 |
| Others | 0.72 | 0.51 | 1.03 | 0.073 | 0.94 | 0.58 | 1.51 | 0.786 |
| Period | ||||||||
| <1995 | Reference category | Reference category | ||||||
| 1995–1998 | 1.08 | 0.86 | 1.36 | 0.510 | 1.00 | 0.74 | 1.34 | 0.988 |
| 1999–2004 | 0.74 | 0.62 | 0.88 | 0.001 | 0.59 | 0.47 | 0.75 | <0.001 |
| ≥2005 | 0.59 | 0.49 | 0.73 | <0.001 | 0.41 | 0.30 | 0.55 | <0.001 |
Fig. 3.
Kaplan Meier of univariate analysis of DFS (A) and OS (B) in the matched population.
3.3. Prognostic value of age ≤35 - multivariate survival analysis
In a multivariate analysis including age, CT, ER, ET, grade, tumoral size, lymph node involvement, LVI, histological type, and period of diagnostic, age ≤35 was significantly associated with worse DFS [HR 1.56, 95%CI 1.32–1.84, p < 0.001] and OS [HR 1.29, 95%CI 1.03–1.60, p = 0.025] (Table 2, Fig. 3). Other independent prognostic factors were grade, tumor size, pN + macro, LVI, period after 1999, and ER-negativity (for OS only) (Table 3). In a multivariate analysis adjusted on all the previous variable and on molecular subtypes, independent negative value of age was maintained for DFS only but not OS (Supplementary Table 1).
Table 3.
Impact of young age on DFS and OS in the different analysis: univariate, multivariate and matched multivariate.
| Analysis | DFS |
OS |
||||||
|---|---|---|---|---|---|---|---|---|
| 95%CI |
95%CI |
|||||||
| HR | min | max | p value | HR | min | max | p value | |
| Univariate | 1.90 | 1.63 | 2.22 | <0.001 | 1.76 | 1.43 | 2.17 | <0.001 |
| Multivariate | 1.56 | 1.32 | 1.84 | <0.001 | 1.29 | 1.03 | 1.60 | 0.025 |
| Matched | 1.56 | 1.28 | 1.91 | <0.001 | 1.33 | 1.02 | 1.73 | 0.032 |
3.4. Prognostic value of age ≤35 - matched population
In the 1 to 3 matched cohort (457 patients ≤35 for 1368 aged 36–50), Log-rank tests stratified on the pairs revealed a significant unfavorable impact of age ≤35 on survivals. 5- and 10-year DFS in ≤35 versus 36–50 were of 75% [95%IC 71.13–79.06] versus 85% [95%IC 83.36–86.64], and 60% [95%IC 55.20–64.20] versus 68% [95%IC 65.86–70.14], p < 0.001; 5- and 10-years OS were of 89% [95%IC 85.91–91.69] versus 92% [95%IC 91.18–93.62] and 76% [95%IC 71.77–79.63] versus 80% [95%IC 77.96–81.64], p = 0.031 (Fig. 4). HR for young age was 1.56 [95%CI 1.28–1.91; p < 0.001] for DFS and 1.33 [95%CI 1.02–1.73; p = 0.032] for OS (Table 2, Fig. 3).
Fig. 4.
Impact of young age on DFS and OS: summary of Hazard Ratio by Forest plot.
3.5. Analyses focused on the ≤35 years cohort
The cohort of ≤35 years patients was analyzed according to ER status and molecular subtypes (Table 4). Among the 556 patients, 211 presented ER- and 345 ER + tumors. Molecular subtype was available in 329 patients: 139 luminal-A; 31 HER2-positive; 61 triple-negative; 52 luminal-B HER2-negative; 46 luminal-B HER2-positive. Period of diagnostic, grade, HER2 status, lymph node treatment and status, surgery type, adjuvant CT, and ET, were significantly different according to ER status and molecular subtype.
Table 4.
Characteristics of ≤35 according to endocrine receptors and molecular subtype.
| ≤35 y CHARACTERISTICS | Total | ER- (n = 211) |
ER+ (n = 345) |
p value | Total | LumA (139) |
HER2+ [31] |
TN (61) |
LumB G3 (52) |
LumB HER2+ (46) |
p value | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | n | % | n | % | n | % | n | % | ||||||
| Period | 556 | 211 | 345 | <0.001 | 329 | 139 | 31 | 61 | 52 | 46 | 0.048 | ||||||||
| Before 2005 | 156 | 74% | 178 | 52% | 45 | 32% | 10 | 32% | 32 | 52% | 21 | 40% | 13 | 28% | |||||
| After 2005 | 55 | 26% | 167 | 48% | 94 | 68% | 21 | 68% | 29 | 48% | 31 | 60% | 33 | 72% | |||||
| Tumor size in mm | 542 | 208 | 334 | 0.799 | 321 | 133 | 30 | 61 | 52 | 45 | 0.43 | ||||||||
| ≤5 | 16 | 8% | 22 | 7% | 9 | 7% | 4 | 13% | 6 | 10% | 4 | 8% | 2 | 4% | |||||
| 6 to 10 | 29 | 14% | 54 | 16% | 24 | 18% | 5 | 17% | 5 | 8% | 4 | 8% | 9 | 20% | |||||
| 11 to 20 | 92 | 44% | 138 | 41% | 60 | 45% | 13 | 43% | 26 | 43% | 22 | 42% | 15 | 33% | |||||
| >20 | 71 | 34% | 120 | 36% | 40 | 30% | 8 | 27% | 24 | 39% | 22 | 42% | 19 | 42% | |||||
| Histological type | 556 | 211 | 345 | 0.075 | 329 | 139 | 31 | 61 | 52 | 46 | 0.084 | ||||||||
| Ductal | 184 | 87% | 309 | 90% | 119 | 86% | 31 | 100% | 53 | 87% | 49 | 94% | 45 | 98% | |||||
| Lobular | 9 | 4% | 19 | 6% | 10 | 7% | 0 | 0% | 1 | 2% | 1 | 2% | 1 | 2% | |||||
| Mixed | 1 | 0% | 5 | 1% | 4 | 3% | 0 | 0% | 1 | 2% | 0 | 0% | 0 | 0% | |||||
| Other | 17 | 8% | 12 | 3% | 6 | 4% | 0 | 0% | 6 | 10% | 2 | 4% | 0 | 0% | |||||
| SBR grade | 527 | 194 | 333 | <0.001 | 323 | 137 | 30 | 58 | 52 | 46 | <0.001 | ||||||||
| 1 | 18 | 9% | 42 | 13% | 30 | 22% | 1 | 3% | 6 | 10% | 0 | 0% | 1 | 2% | |||||
| 2 | 55 | 28% | 185 | 56% | 107 | 78% | 12 | 40% | 7 | 12% | 0 | 0% | 20 | 43% | |||||
| 3 | 121 | 62% | 106 | 32% | 0 | 0% | 17 | 57% | 45 | 78% | 52 | 100% | 25 | 54% | |||||
| Endocrine Receptor | 556 | 211 | 345 | 329 | 139 | 31 | 61 | 52 | 46 | <0.001 | |||||||||
| Negative | 211 | 100% | 0 | 0% | 0 | 0% | 31 | 100% | 61 | 100% | 0 | 0% | 0 | 0% | |||||
| Positive | 0 | 0% | 345 | 100% | 139 | 100% | 0 | 0% | 0 | 0% | 52 | 100% | 46 | 100% | |||||
| Estrogen receptor | 478 | 163 | 315 | <0.001 | 326 | 139 | 30 | 60 | 51 | 46 | <0.001 | ||||||||
| Negative | 163 | 100% | 17 | 5% | 3 | 2% | 30 | 100% | 60 | 100% | 1 | 2% | 2 | 4% | |||||
| Positive | 0 | 0% | 298 | 95% | 136 | 98% | 0 | 0% | 0 | 0% | 50 | 98% | 44 | 96% | |||||
| Progesterone receptor | 467 | 161 | 306 | <0.001 | 318 | 135 | 30 | 60 | 48 | 45 | <0.001 | ||||||||
| Negative | 161 | 100% | 24 | 8% | 6 | 4% | 30 | 100% | 60 | 100% | 8 | 17% | 4 | 9% | |||||
| Positive | 0 | 0% | 282 | 92% | 129 | 96% | 0 | 0% | 0 | 0% | 40 | 83% | 41 | 91% | |||||
| HER2 overexpressed | 329 | 92 | 237 | <0.001 | 329 | 139 | 31 | 61 | 52 | 46 | <0.001 | ||||||||
| No | 61 | 66% | 191 | 81% | 139 | 100% | 0 | 0% | 61 | 100% | 52 | 100% | 0 | 0% | |||||
| Yes | 31 | 34% | 46 | 19% | 0 | 0% | 31 | 100% | 0 | 0% | 0 | 0% | 46 | 100% | |||||
| SLNB and/or ALND | 554 | 209 | 345 | <0.001 | 329 | 139 | 31 | 61 | 52 | 46 | 0.015 | ||||||||
| SLNB | 42 | 20% | 113 | 33% | 64 | 46% | 8 | 26% | 27 | 44% | 18 | 35% | 17 | 37% | |||||
| SLNB + ALND | 35 | 17% | 117 | 34% | 60 | 43% | 14 | 45% | 16 | 26% | 20 | 38% | 21 | 46% | |||||
| ALND | 132 | 63% | 115 | 33% | 15 | 11% | 9 | 29% | 18 | 30% | 14 | 27% | 8 | 17% | |||||
| Final lymph node status | 549 | 208 | 341 | 0.002 | 324 | 135 | 31 | 60 | 52 | 46 | 0.018 | ||||||||
| pN0 | 117 | 56% | 158 | 46% | 69 | 51% | 13 | 42% | 35 | 58% | 19 | 37% | 23 | 50% | |||||
| pN0(i+) | 4 | 2% | 19 | 6% | 10 | 7% | 1 | 3% | 2 | 3% | 5 | 10% | 1 | 2% | |||||
| pN1mi | 5 | 2% | 30 | 9% | 20 | 15% | 3 | 10% | 2 | 3% | 1 | 2% | 5 | 11% | |||||
| pN1macro | 82 | 39% | 134 | 39% | 36 | 27% | 14 | 45% | 21 | 35% | 27 | 52% | 17 | 37% | |||||
| LVI | 491 | 187 | 304 | 0.646 | 297 | 125 | 27 | 58 | 47 | 40 | 0.268 | ||||||||
| No | 88 | 47% | 156 | 51% | 79 | 63% | 16 | 59% | 36 | 62% | 20 | 43% | 20 | 50% | |||||
| Yes | 99 | 53% | 148 | 49% | 46 | 37% | 11 | 41% | 22 | 38% | 27 | 57% | 20 | 50% | |||||
| Surgery type | 548 | 209 | 339 | 0.002 | 322 | 137 | 29 | 61 | 49 | 46 | 0.008 | ||||||||
| Lumpectomy | 162 | 78% | 215 | 63% | 71 | 52% | 14 | 48% | 43 | 70% | 29 | 59% | 34 | 74% | |||||
| Mastectomy | 47 | 22% | 124 | 37% | 66 | 48% | 15 | 52% | 18 | 30% | 20 | 41% | 12 | 26% | |||||
| Adjuvant CT | 556 | 211 | 345 | 0.005 | 329 | 139 | 31 | 61 | 52 | 46 | 0.001 | ||||||||
| No | 47 | 22% | 46 | 13% | 26 | 19% | 2 | 6% | 3 | 5% | 0 | 0% | 2 | 4% | |||||
| Yes | 160 | 76% | 281 | 81% | 106 | 76% | 27 | 87% | 56 | 92% | 48 | 92% | 37 | 80% | |||||
| Neo-adjuvant | 4 | 2% | 18 | 5% | 7 | 5% | 2 | 6% | 2 | 3% | 4 | 8% | 7 | 15% | |||||
| Trastuzumab | 536 | 206 | 330 | 0.163 | 308 | 125 | 27 | 60 | 51 | 45 | <0.001 | ||||||||
| No | 188 | 91% | 291 | 88% | 125 | 100% | 10 | 37% | 60 | 100% | 51 | 100% | 9 | 20% | |||||
| Yes | 18 | 9% | 39 | 12% | 17 | 63% | 36 | 80% | |||||||||||
| RT | 539 | 203 | 336 | 0.575 | 315 | 135 | 30 | 55 | 52 | 43 | 0.091 | ||||||||
| No | 13 | 6% | 27 | 8% | 18 | 13% | 5 | 17% | 5 | 9% | 5 | 10% | 1 | 2% | |||||
| Yes | 190 | 94% | 309 | 92% | 117 | 87% | 25 | 83% | 50 | 91% | 47 | 90% | 42 | 98% | |||||
| ET | 547 | 202 | 345 | <0.001 | 326 | 139 | 30 | 59 | 52 | 46 | <0.001 | ||||||||
| No | 202 | 100% | 40 | 12% | 11 | 8% | 30 | 100% | 59 | 100% | 3 | 6% | 4 | 9% | |||||
| Yes | 305 | 88% | 128 | 92% | 49 | 94% | 42 | 91% | |||||||||||
| Relapse type | 187 | 88 | 99 | 0.08 | 81 | 24 | 10 | 16 | 23 | 8 | 0.386 | ||||||||
| Axillary | 1 | 1% | 5 | 5% | 1 | 4% | 1 | 10% | 0 | 0% | 1 | 4% | 1 | 13% | |||||
| Metastatic | 59 | 67% | 61 | 62% | 15 | 63% | 6 | 60% | 8 | 50% | 17 | 74% | 5 | 63% | |||||
| Other | 17 | 19% | 21 | 21% | 4 | 17% | 2 | 20% | 4 | 25% | 3 | 13% | 2 | 25% | |||||
| Contro lateral | 5 | 6% | 11 | 11% | 4 | 17% | 0 | 0% | 1 | 6% | 2 | 9% | 0 | 0% | |||||
| Unknown | 6 | 7% | 1 | 1% | 0 | 0% | 1 | 10% | 3 | 19% | 0 | 0% | 0 | 0% | |||||
ER-patients had more grade 3 (62% versus 32% in ER+), HER2+ (34% versus 19%), ALND (63% versus 33%), and pN0 (56% versus 46%). In the ER+, we observed more mastectomy (37% versus 22% in ER-) and adjuvant CT (81% versus 76%).
Triple-negative subgroup presented more grade 3 (78%), and CT use (92%). The luminal-B HER2-negative subgroup presents more pN + macro (52%), and LVI (57%).
In univariate analyses according to ER (Fig. 5), ER + group presented a better 5-year DFS [79%; 95%CI 75.40–82.20] and OS [94%; 95%CI 91.79–95.80] than 5-year DFS [67%; 95%CI 63.40–71.20] and OS [82%; 95%CI 78.91–85.29] in ER-group; p = 0.002 for DFS; p < 0.001 for OS.
Fig. 5.
Kaplan Meier of univariate analysis of DFS (A) and OS (B) in the <35 cohort according to endocrine receptors.
In univariate analyses according to molecular subtype (Fig. 6), 5-year DFS were: 91% [95%CI 87.45–93.75] for luminal-A; 81% [95%CI 77.09–85.51] for luminal-B HER2-positive; 76% [95%CI 71.49–80.71] for triple-negative; 76% [95%CI 71.06–80.33] for HER2-positive; 63% [95%CI 58.09–68.51] for luminal-B HER2-negative; p = 0.003. The 5-year OS were: 98% [95%CI 96.62–99.57] for luminal-A; 98% [95%CI 96.08–99.32] for luminal-B HER2-positive; 89% [95%CI 85.39–92.21] for HER2-positive; 87% [95%CI 82.92–90.28] for triple-negative; 84% [95%CI 79.82–87.78] for luminal-B HER2-negative; p < 0.001.
Fig. 6.
Kaplan Meier of univariate analysis of DFS (A) and OS (B) in the <35 cohort according to molecular subtype.
In a new multivariate analysis based on the same parameters focused on ≤35 group, we observed a significative association with worse DFS and OS for pN + macro, ER-, LVI, and lobular type (for DFS only). SBR grade, ET, and adjuvant CT were not independently associated with survivals (Table 5).
Table 5.
Multivariate analysis of DFS and OS in the ≤35 cohort.
| DFS |
OS |
|||||||
|---|---|---|---|---|---|---|---|---|
| ≤35 ONLY |
HR |
95% CI |
p value |
HR |
95% CI |
p value |
||
| min | max | min | max | |||||
| CT | ||||||||
| No | Reference category | Reference category | ||||||
| Adjuvant | 0,71 | 0,46 | 1,11 | 0,136 | 0,59 | 0,32 | 1,08 | 0,085 |
| Neo-adjuvant | 0,35 | 0,12 | 1,05 | 0,062 | 0,41 | 0,11 | 1,56 | 0,192 |
| ER | 0,50 | 0,28 | 0,89 | 0,019 | 0,45 | 0,22 | 0,92 | 0,029 |
| ET | 0,21 | 0,69 | 2,21 | 0,476 | 0,91 | 0,44 | 1,87 | 0,796 |
| SBR grade | ||||||||
| 1 | Reference category | Reference category | ||||||
| 2 | 1,30 | 0,72 | 2,35 | 0,383 | 1,41 | 0,59 | 3,39 | 0,445 |
| 3 | 1,27 | 0,69 | 2,34 | 0,448 | 1,77 | 0,73 | 4,28 | 0,205 |
| Size (mm) | ||||||||
| ≤5 | Reference category | Reference category | ||||||
| 5 to 10 | 0,34 | 0,15 | 0,75 | 0,008 | 0,18 | 0,06 | 0,58 | 0,004 |
| 10 to 20 | 0,59 | 0,29 | 1,20 | 0,146 | 0,37 | 0,14 | 0,96 | 0,041 |
| 20 to 50 | 0,69 | 0,34 | 1,37 | 0,287 | 0,63 | 0,25 | 1,55 | 0,310 |
| >50 | 1,07 | 0,45 | 2,56 | 0,881 | 0,70 | 0,22 | 2,19 | 0,538 |
| Lymph node involvement | ||||||||
| pN0 | Reference category | Reference category | ||||||
| pN0(i+) | 1,01 | 0,40 | 2,56 | 0,976 | 0,92 | 0,21 | 3,93 | 0,909 |
| pN + mi | 0,52 | 0,20 | 1,31 | 0,165 | 0,60 | 0,14 | 2,60 | 0,497 |
| pN + macro | 1,54 | 1,07 | 2,20 | 0,019 | 1,91 | 1,16 | 3,14 | 0,011 |
| LVI | ||||||||
| No | Reference category | Reference category | ||||||
| Yes | 1,66 | 1,16 | 2,38 | 0,005 | 2,21 | 1,32 | 3,69 | 0,003 |
| Unknown | 1,77 | 1,07 | 2,94 | 0,027 | 1,75 | 0,85 | 3,59 | 0,130 |
| Histological type | ||||||||
| Ductal | Reference category | Reference category | ||||||
| Lobular | 3,48 | 1,89 | 6,39 | <0.001 | 2,20 | 0,84 | 5,75 | 0,107 |
| Mixed | 0,00 | 0,00 | 0,00 | 0,952 | 0,00 | 0,00 | 0,00 | 0,967 |
| Others | 0,82 | 0,35 | 1,90 | 0,643 | 0,61 | 0,14 | 2,54 | 0,495 |
4. Discussion
Our results support the poor prognosis value of young age, which persisted when adjusting for other prognostic factors and treatments, whether in multivariate or in matched populations.
Patients ≤35 had more severe tumor presentations and poorer survival than 36–50 patients. Young age was associated with larger tumors, higher grade, more LVI, ER-negativity, HER2-positivity, and macroscopic lymph node involvement. These unfavorable factors were associated with more aggressive treatment strategies, with higher rate of ALND, mastectomy, and systemic treatments. Tumor subtype was also affected by age category with more triple-negative (19%), luminal-B (30%) and HER2-positive (9%) tumors in the ≤35 cohort compared to the 36–50.
The literature review is challenged by the lack of homogeneity in the definition of “young woman” in previous studies dealing with the clinicopathological and molecular characteristics of BC. Some of the articles define young age as <35 years, while others focus on women <40 years. As for the control group, the challenge was to select an older group which was comparable regarding menopausal status. The upper boundary of 50 years was retained as estimated median age at menopause are 50.31 and 51.5 years in large historical retrospective and prospective cohorts [14,15]. Data on CT-induced amenorrhea or perimenopausal status were not known. Our observations are consistent with previous studies supporting the association of young age with unfavorable prognostic factors at presentation such as larger tumor size [[16], [17], [18], [19]], increased macroscopic lymph node involvement [[17], [18], [19]], increased LVI-positivity [18,20], grade 3 [[16], [17], [18], [19]], ER-negativity [17,18], as well as more aggressive treatments [17,[21], [22], [23]]. In our study, HER2 overexpression was more prevalent in young patients (23% versus 11%), consistently with previous reports. Cancello et al. reported HER2-positivity in 21% oy young patients versus 14% in older (p < 0.003) [18], Anders et al. reported 29% of HER2-positivity in women <40 years versus 22% in patients ≤45 years and only 14% in those ≥65 years (Duke dataset) [24]. Similar findings were reported by Kim et al. with a 10% positivity rate in women ≤40 years versus 7% in older women (p < 0.004) [25]. The distribution of BC subtypes in our study is also consistent with previous reports with respectively 23% and 18% [26], and 21% and 25% [27] of triple-negative and luminal-B in young women.
DFS and OS were negatively impacted by young age. The 5-years DFS and OS in the ≤35 cohort (74% and 89%, respectively) were close to the 10-years DFS and OS in the 36–50 patients (74% and 85%, respectively). In multivariate analyses, age ≤35 was associated to worse DFS (HR1.56; p < 0.001) and OS (HR1.29; p = 0.025), as well as in the case-control matched analysis (DFS (HR1.56; p < 0.001) and OS (HR1.33; p = 0.032)). Consistently, recent periods were associated with better survival, reflecting advances in BC management. In our multivariate analysis including molecular subtypes, independent value of age was only maintained for DFS but not for OS, probably because of the loss of power. The negative impact of young age is consistent with other studies where patients <35 present worse survival, even after adjustment on tumor characteristics and treatments. The largest series to date is derived from a Japanese registry of women treated from 2004 to 2006, confirming the prognostic impact of age (<35 (n = 736) versus 35–50 versus >50 years) to the disadvantage of younger patients for both DFS (HR1.73; p < 0.001) and OS (HR 1.58; p = 0.004) [28]. Kroman et al. included 867 patients <35 years [19]. In the absence of adjuvant therapy, younger age was correlated with a higher risk of death with a relative risk of 2.18 compared to patients aged 45–49 years. To be noted that in this series the negative impact disappeared in case of adjuvant CT. Consistently, Peng et al. describes worse DFS than in older patients, even after adjustment on tumor characteristics and treatments (HR1.64, p < 0.001) [29]. Early stages and small tumors, where treatment can be discussed, were associated with decreased survival [16]. Age ≤35 could even be considered by some authors as the second most powerful independent risk factor after lymph node status [30,31]. As in a similar study using a propensity score on 365 women ≤40 years [32], we can consider age ≤35 as an independent factor of poor prognosis in early BC. Altogether, the negative prognostic role of young age is confirmed in multivariate analysis in most studies. These conclusions are discordant with latest ESMO's recommendations [7], and should be considered in the decision making for therapeutical strategies in young patients.
Our analyses focusing on the ≤35 years cohort identified ER-negativity, lymph node involvement, LVI and lobular type as independent prognostic factors, consistently with previous reports [[33], [34], [35], [36]]. Lobular type was associated with worse DFS but had no impact on OS in the ≤35 cohort, possibly explained by the high rate of local recurrence [37]. As previously reported, lobular subtype was less frequent in young patients [6,18]. Multivariate analysis showed peculiarly that grade, ET, and adjuvant CT were not significantly associated with survival. This might be linked to a lack of power, limited follow up, as well as poorer compliance with ET in younger women [38]. The most unfavorable subtypes in our analysis were luminal-B HER2-negative and triple-negative BC. In this situation, grade may predominate over ER and HER2.
Our study has limitations. Among them, absence of BRCA status is a key. Approximately 12% of BC arising in women aged ≤40 years are related to germline pathogenic variants in BRCA1 or BRCA2 gene [39,40]. BRCA-related BC may have different biological characteristics, with increased triple-negative subtype in BRCA1 carriers and more luminal subtypes in BRCA2 carriers [41]. The detail about precise chemotherapy regimen for each patient was not available in our database. Patients were treated at 15 centers and adjuvant treatments may have differed. However, this multicenter cohort reflects clinical reality out of clinical trials. Despite careful methodology to minimize bias, the second major limitation of our study is its retrospective design. However, we have the advantages of limiting biases inherent in single-center studies while also reflecting real-world practice.
5. Conclusion
Our results support the independent poor prognosis value of young age, which persisted when adjusting for other prognostic factors and treatments. Early BC in young patients ≤35 years old is associated with less favorable presentation and more aggressive treatment strategies. Luminal-B, triple-negative and HER2-positive subtypes are overrepresented compared to luminal-A.
Ethics approval
This cohort study was approved by our institutional review board. All procedures performed in this study involving human participants were done in accordance with the French ethical standards and with the 2008 Helsinki declaration.
Funding
This academic work did not receive financial support from any funding source.
Declaration of competing interest
Alexandre de Nonneville declares Gilead (lecture fees, congress invitations), Daiichi Sankyo (lecture fees, congress invitations), Seagen (consulting fees), Lilly (lecture fees, congress invitations, consulting fees, research grants paid to institution), Novartis (consulting fees), MSD (congress invitations, lecture fees), Pfizer (research grants paid to institution). No conflict of interest declared by others authors.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2023.02.004.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
- 1.Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer statistics, 2021. Ca - Cancer J Clin. 2021;71(1):7–33. doi: 10.3322/caac.21654. [DOI] [PubMed] [Google Scholar]
- 2.Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca - Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 3.Nixon A.J., Neuberg D., Hayes D.F., Gelman R., Connolly J.L., Schnitt S., et al. Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. mai. 1994;12(5):888–894. doi: 10.1200/JCO.1994.12.5.888. [DOI] [PubMed] [Google Scholar]
- 4.de la Rochefordiere A., Asselain B., Campana F., Scholl S.M., Fenton J., Vilcoq J.R., et al. Age as prognostic factor in premenopausal breast carcinoma. Lancet Lond Engl. 24 avr. 1993;341(8852):1039–1043. doi: 10.1016/0140-6736(93)92407-k. [DOI] [PubMed] [Google Scholar]
- 5.Albain K.S., Allred D.C., Clark G.M. Breast cancer outcome and predictors of outcome: are there age differentials? J Natl Cancer Inst Monogr. 1994;(16):35–42. [PubMed] [Google Scholar]
- 6.Han W., Kim S.W., Park I.A., Kang D., Kim S.W., Youn Y.K., et al. Young age: an independent risk factor for disease-free survival in women with operable breast cancer. BMC Cancer. 2004;4:82. doi: 10.1186/1471-2407-4-82. 17 nov. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Paluch-Shimon S., Cardoso F., Partridge A.H., Abulkhair O., Azim H.A., Bianchi-Micheli G., et al. ESO–ESMO 4th international consensus guidelines for breast cancer in young women (BCY4) Ann Oncol. 1 juin. 2020;31(6):674–696. doi: 10.1016/j.annonc.2020.03.284. [DOI] [PubMed] [Google Scholar]
- 8.Paluch-Shimon S., Pagani O., Partridge A.H., Abulkhair O., Cardoso M.J., Dent R.A., et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3) Breast Edinb Scotl. oct 2017;35:203–217. doi: 10.1016/j.breast.2017.07.017. [DOI] [PubMed] [Google Scholar]
- 9.Houvenaeghel G., Cohen M., Classe J.M., Reyal F., Mazouni C., Chopin N., et al. Lymphovascular invasion has a significant prognostic impact in patients with early breast cancer, results from a large, national, multicenter, retrospective cohort study. ESMO Open. déc. 2021;6(6) doi: 10.1016/j.esmoop.2021.100316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Houvenaeghel G., de Nonneville A., Cohen M., Chopin N., Coutant C., Reyal F., et al. Lack of prognostic impact of sentinel node micro-metastases in endocrine receptor-positive early breast cancer: results from a large multicenter cohort. ESMO Open. 10 mai. 2021;6(3) doi: 10.1016/j.esmoop.2021.100151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.de Nonneville A., Jauffret C., Gonçalves A., Classe J.M., Cohen M., Reyal F., et al. Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit. Breast Cancer Res Treat. juin. 2019;175(2):379–387. doi: 10.1007/s10549-019-05160-9. [DOI] [PubMed] [Google Scholar]
- 12.Little R.J., Rubin D.B. Causal effects in clinical and epidemiological studies via potential outcomes: concepts and analytical approaches. Annu Rev Publ Health. 2000;21:121–145. doi: 10.1146/annurev.publhealth.21.1.121. [DOI] [PubMed] [Google Scholar]
- 13.Rosenbaum P.R. Modern algorithms for matching in observational studies. Annu Rev Stat Its Appl. 2020;7(1):143–176. [Google Scholar]
- 14.Bromberger J.T., Matthews K.A., Kuller L.H., Wing R.R., Meilahn E.N., Plantinga P. Prospective study of the determinants of age at menopause. Am J Epidemiol. 15 janv. 1997;145(2):124–133. doi: 10.1093/oxfordjournals.aje.a009083. [DOI] [PubMed] [Google Scholar]
- 15.Gottschalk M.S., Eskild A., Hofvind S., Gran J.M., Bjelland E.K. Temporal trends in age at menarche and age at menopause: a population study of 312 656 women in Norway. Hum Reprod. 29 févr. 2020;35(2):464–471. doi: 10.1093/humrep/dez288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Fredholm H., Eaker S., Frisell J., Holmberg L., Fredriksson I., Lindman H. Breast cancer in young women: poor survival despite intensive treatment. PLoS One. 2009;4(11) doi: 10.1371/journal.pone.0007695. 11 nov. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gnerlich J.L., Deshpande A.D., Jeffe D.B., Sweet A., White N., Margenthaler J.A. Elevated breast cancer mortality in young women (<40 Years) compared with older women is attributed to poorer survival in early stage disease. J Am Coll Surg. mars. 2009;208(3):341–347. doi: 10.1016/j.jamcollsurg.2008.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cancello G., Maisonneuve P., Rotmensz N., Viale G., Mastropasqua M.G., Pruneri G., et al. Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer. Ann Oncol Off J Eur Soc Med Oncol. oct. 2010;21(10):1974–1981. doi: 10.1093/annonc/mdq072. [DOI] [PubMed] [Google Scholar]
- 19.Kroman N., Jensen M.B., Wohlfahrt J., Mouridsen H.T., Andersen P.K., Melbye M. Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ. 19 févr. 2000;320(7233):474–478. doi: 10.1136/bmj.320.7233.474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Colleoni M., Rotmensz N., Robertson C., Orlando L., Viale G., Renne G., et al. Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol Off J Eur Soc Med Oncol. févr. 2002;13(2):273–279. doi: 10.1093/annonc/mdf039. [DOI] [PubMed] [Google Scholar]
- 21.Kothari A.S., Beechey-Newman N., D'Arrigo C., Hanby A.M., Ryder K., Hamed H., et al. Breast carcinoma in women age 25 years or less. Cancer. 1 févr. 2002;94(3):606–614. doi: 10.1002/cncr.10273. [DOI] [PubMed] [Google Scholar]
- 22.Bharat A., Aft R.L., Gao F., Margenthaler J.A. Patient and tumor characteristics associated with increased mortality in young women (≤40 years) with breast cancer. J Surg Oncol. 2009;100(3):248–251. doi: 10.1002/jso.21268. [DOI] [PubMed] [Google Scholar]
- 23.Chung W.P., Lee K.T., Chen Y.P., Hsu Y.T., Loh Z.J., Huang C.C., et al. The prognosis of early-stage breast cancer in extremely young female patients. Medicine (Baltimore). 8 janv. 2021;100(1) doi: 10.1097/MD.0000000000024076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Anders C.K., Hsu D.S., Broadwater G., Acharya C.R., Foekens J.A., Zhang Y., et al. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol. 10 juill. 2008;26(20):3324–3330. doi: 10.1200/JCO.2007.14.2471. [DOI] [PubMed] [Google Scholar]
- 25.Kim H.J., Han W., Yi O.V., Shin H.C., Ahn S.K., Koh B.S., et al. Young age is associated with ipsilateral breast tumor recurrence after breast conserving surgery and radiation therapy in patients with HER2-positive/ER-negative subtype. Breast Cancer Res Treat. 2011;130(2):499–505. doi: 10.1007/s10549-011-1736-3. 1 nov. [DOI] [PubMed] [Google Scholar]
- 26.Collins L.C., Marotti J.D., Gelber S., Cole K., Ruddy K., Kereakoglow S., et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat. 1 févr. 2012;131(3):1061–1066. doi: 10.1007/s10549-011-1872-9. [DOI] [PubMed] [Google Scholar]
- 27.Keegan T.H.M., DeRouen M.C., Press D.J., Kurian A.W., Clarke C.A. Occurrence of breast cancer subtypes in adolescent and young adult women. Breast Cancer Res. 27 mars 2012;14(2):R55. doi: 10.1186/bcr3156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kataoka A., Iwamoto T., Tokunaga E., Tomotaki A., Kumamaru H., Miyata H., et al. Young adult breast cancer patients have a poor prognosis independent of prognostic clinicopathological factors: a study from the Japanese Breast Cancer Registry. Breast Cancer Res Treat. 2016;160(1):163–172. doi: 10.1007/s10549-016-3984-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Peng R., Wang S., Shi Y., Liu D., Teng X., Qin T., et al. Patients 35 years old or younger with operable breast cancer are more at risk for relapse and survival: a retrospective matched case-control study. Breast Edinb Scotl. déc. 2011;20(6):568–573. doi: 10.1016/j.breast.2011.07.012. [DOI] [PubMed] [Google Scholar]
- 30.Martínez M.T., Oltra S.S., Peña-Chilet M., Alonso E., Hernando C., Burgues O., et al. Breast cancer in very young patients in a Spanish cohort: age as an independent bad prognostic indicator. Breast Cancer Basic Clin Res. 20 févr. 2019;13 doi: 10.1177/1178223419828766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Dubsky P.C., Gnant M.F.X., Taucher S., Roka S., Kandioler D., Pichler-Gebhard B., et al. Young age as an independent adverse prognostic factor in premenopausal patients with breast cancer. Clin Breast Cancer. avr. 2002;3(1):65–72. doi: 10.3816/CBC.2002.n.013. [DOI] [PubMed] [Google Scholar]
- 32.Zhong W., Tan L., Jiang W.G., Chen K., You N., Sanders A.J., et al. Effect of younger age on survival outcomes in T1N0M0 breast cancer: a propensity score matching analysis. J Surg Oncol. 2019;119(8):1039–1046. doi: 10.1002/jso.25457. [DOI] [PubMed] [Google Scholar]
- 33.Fu J., Zhong C., Wu L., Li D., Xu T., Jiang T., et al. Young patients with hormone receptor-positive breast cancer have a higher long-term risk of breast cancer specific death. J Breast Cancer. mars. 2019;22(1):96–108. doi: 10.4048/jbc.2019.22.e13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Partridge A.H., Gelber S., Piccart-Gebhart M.J., Focant F., Scullion M., Holmes E., et al. Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2–positive breast cancer: results from a herceptin adjuvant trial. J Clin Oncol. 10 juin. 2013;31(21):2692–2698. doi: 10.1200/JCO.2012.44.1956. [DOI] [PubMed] [Google Scholar]
- 35.Bacchi L.M., Corpa M., Santos P.P., Bacchi C.E., Carvalho F.M. Estrogen receptor-positive breast carcinomas in younger women are different from those of older women: a pathological and immunohistochemical study. Breast Edinb Scotl. avr. 2010;19(2):137–141. doi: 10.1016/j.breast.2010.01.002. [DOI] [PubMed] [Google Scholar]
- 36.Copson E., Eccles B., Maishman T., Gerty S., Stanton L., Cutress R.I., et al. Prospective observational study of breast cancer treatment outcomes for UK women aged 18–40 Years at diagnosis: the POSH study. JNCI J Natl Cancer Inst. 3 juill. 2013;105(13):978–988. doi: 10.1093/jnci/djt134. [DOI] [PubMed] [Google Scholar]
- 37.Neri A., Marrelli D., Megha T., Bettarini F., Tacchini D., De Franco L., et al. Clinical significance of multifocal and multicentric breast cancers and choice of surgical treatment: a retrospective study on a series of 1158 cases. BMC Surg. 14 janv. 2015;15(1):1. doi: 10.1186/1471-2482-15-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Rosenberg S.M., Partridge A.H. Management of breast cancer in very young women. Breast Edinb Scotl. nov. 2015;24(Suppl 2):S154–S158. doi: 10.1016/j.breast.2015.07.036. [DOI] [PubMed] [Google Scholar]
- 39.Copson E.R., Maishman T.C., Tapper W.J., Cutress R.I., Greville-Heygate S., Altman D.G., et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. févr. 2018;19(2):169–180. doi: 10.1016/S1470-2045(17)30891-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Rosenberg S.M., Ruddy K.J., Tamimi R.M., Gelber S., Schapira L., Come S., et al. BRCA1 and BRCA2 mutation testing in young women with breast cancer. JAMA Oncol. 1 juin. 2016;2(6):730–736. doi: 10.1001/jamaoncol.2015.5941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Lambertini M., Ceppi M., Hamy A.S., Caron O., Poorvu P.D., Carrasco E., et al. Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants. NPJ Breast Cancer. 12 févr. 2021;7(1):16. doi: 10.1038/s41523-021-00224-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.