|Ahead of print publication
Breast cancer in young and very young women; is age related to outcome?
Okan Avci, Seher Yildiz Tacar, Erdogan Selçuk Seber, Tarkan Yetisyigit
Department of Medical Oncology, Namik Kemal University, Tekirdağ, Turkey
|Date of Submission||28-Apr-2020|
|Date of Decision||16-Jul-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||16-Jul-2021|
Medical Oncology Clinic, Namik Kemal University, Süleymanpasa, Tekirdag
Source of Support: None, Conflict of Interest: None
Background: Breast cancer in young women is associated with aggressive biology. We analyzed histopathological and clinical properties of breast cancer patients diagnosed at ≤40 years of age.
Methods: Breast cancer patients who were admitted between 2015 and 2019 were included. Baseline characteristics of the patients with treatment-related outcomes were assessed. The study group was divided into two subgroups; <35 years old as “very young” and ≥35 years old as “young.”
Results: The data of 137 patients (60 patients <35 years) were reviewed. The mean age was 34.7 years. The mean follow-up duration was 44.45 ± 26.39 months, and the mean disease-free survival was 36.17 ± 21.97 months. 11.4% of the patients were diagnosed with Stage 4 disease. Pathologic subtype was invasive ductal carcinoma in 86% of patients. 16.8% of the patients were luminal A, 38.7% luminal B, 30.5% were human epidermal growth factor receptor-2–positive type, and 15.3% were triple-negative. Only 5 (3.3%) patients had given birth after chemotherapy. During the follow-up period of early-staged diagnosed patients, metastatic disease occurred in 24.6%. The rate of distant metastasis development was statistically higher in the very young group (31% vs. 11%; P = 0.004). Thirteen patients (10.7%) died due to disease progression. Thirty-seven percent of the patients had a positive family history for either breast or ovarian cancer.
Conclusions: Very young breast cancer patients seem to have a more aggressive disease course. The low rate of childbearing in this young patient population is conspicuous. An interdisciplinary approach for the management of this special patient population should be taken into consideration.
Keywords: Breast cancer, fertility, molecular subtypes, prognosis, young age
| > Introduction|| |
Breast cancer is the second most common cancer in the world, and more than 2 million cases are diagnosed each year. Moreover, globally, it ranks first in cancer-related deaths among women. Despite the recent high incidence figures, 5-year overall survival (OS) is about 90% in developed countries with the help of both improvements in the treatment options and early diagnosis by screening method.
Breast cancer in young women has worse disease characteristics than in older ages. It is usually diagnosed at a later stage mostly as a result of self-breast examination in symptomatic period since women under the age of 40 are not routinely included in screening programs. In addition, young women with breast cancer have different biological behavioral characteristics compared to older patients; disease course shows more aggressive features and prognosis is worse. The concept of young breast cancer patient is still not clearly defined although the majority of the literature sets the age limit between 35 and 40 years of age.,,,,, The European Society of Breast Cancer Specialists (EUSOMA) Working Group decided to define “young women” as women under the age of 40. Besides having poorer prognosis compared to their older counterparts, women under the age of 40 have age-related specific predicaments in relation to survivorship and fertility issues.
In our study, we aimed to assess the histopathological features and clinical course of breast cancer patients diagnosed at ≤40 years of age who applied to our clinic. As a secondary objective, we aimed to determine whether very young breast cancer patients (<35 years of age) carry discriminating disease-related features compared to their older counterparts.
| > Methods|| |
In this retrospective study, breast cancer patients admitted to the Medical Oncology Department of Namık Kemal University (NKU) between 2015 and 2019 were examined. Before starting the study, ethics committee approval was obtained with 2019.210.11.07 protocol number from the Nondrug Clinical Research Board of NKU. Informed consent was obtained from all patients. All patients with a diagnosis of breast cancer at ≤40 years of age were included in the study group. According to the immunohistochemical evaluation, estrogen receptor (ER) and progesterone receptor (PR) values under 10% were considered as negative. Patients were categorized according to their histological subtypes (luminal A, luminal B, human epidermal growth factor receptor-2 [HER2] type, and triple-negative). ER-, PR-, and HER-2–negative tumors were accepted as triple-negative and HER-2-positive ones as HER2 type. Tumors with Ki-67 expression >20% or grade ≥2 or PR expression level <20% regardless of ER status were categorized as luminal B. All other tumors were considered as luminal A. Demographic information and risk factors were collected with the help of a questionnaire.
SPSS Statistical Package (Version 25 SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Demographic data, risk factors, pathological and molecular variables, and follow-up results were examined in the whole group with the help of descriptive analyses. Mean and standard deviation values were given for parametrically distributed continuous variables. Median and interquartile range values were given for nonparametric continuous variables. Categorical variables were expressed as percentages. Due to nonparametrically distributed continuous variables, Mann–Whitney U-test was used for comparison between two groups. Chi-square test was used for categorical variables.
| > Results|| |
Between May 2015 and June 2019, 1743 breast cancer patients were admitted to our clinic and 137 (7%) of them aged ≤40 years were included in the study. Sixty (43%) patients were aged <35 years. The mean age of the patients was 34.7 years. Median menarche age was 13 and median first birth age was 24. 9.7% of the patients were divorced. Median number of births was 2. Demographics and risk factors for patients are summarized in [Table 1].
In pathologic evaluation of tumors, ER negativity was 24.8% and PR negativity was <20% in 50% of patients. Ki-67 level was above 20% in 60.5% of patients while the median value was 21.5. 77.5% of patients were Grade 2 or above. According to the intrinsic subtype examination, 38.7% of patients were luminal B and 30.5% were HER2 type. The whole pathologic characteristics of the tumors are summarized in [Table 2].
On histological examination; the most common three subtypes were invasive ductal carcinoma - 118 (86%), invasive lobular carcinoma - 5 (3.6%), and ductal carcinoma in situ - 3 (2.3%). On stage evaluation, 62.9% of the patients was ≥pT2, and 39% was pN0. The number of de novo metastatic patients was 14 (11.4%). [Table 3] summarizes the characteristics of stage status at diagnosis.
In the whole group, 132 (99.2%) patients received chemotherapy (CT) as part of curative treatment. CT was applied as a neoadjuvant setting in 33 (25%) of them. Radiotherapy was added in 97 (89.8%) and hormone therapy in 87 (79.1%) patients. As a surgical procedure, 63 (54.8%) patients had breast-conserving surgery.
The family history was questioned. 61.4% of the patients had a family history of cancer. Forty-four (37%) patients had a history of breast and/or ovarian cancer. Sixteen (29%) of these patients were in Group 1 and 28 (43%) of them were in Group 2 (P = 0.69).
The mean follow-up period was 44.45 ± 26.39 months. In the follow-up period after curative treatment, recurrence was occurred in 2.2% of patients as locoregionally and 24.6% as metastatic disease. Metastases' development was significantly higher in very young group (31% vs. 11% and P = 0.004). [Table 4] presents information about patients who recur during the follow-up after primary treatment.
Considering all our patients, the mean disease-free survival (DFS) was 36.17 ± 21.97 months. The mean DFS was 38.32 ± 23.54 months for Group 1 and 34.52 ± 20.68 months for Group 2. The number of patients who become amenorrheic after CT was 24 (17.5%). Five (%3.3) patients had given birth after CT.
| > Discussion|| |
In our study, we aimed to delineate the clinical-pathological features and the follow-up data of cases of breast cancer patients diagnosed at ≤40 years of age. We further analyzed whether patients younger than 35 years have different clinic-pathologic characteristics compared to their older counterparts.
Breast cancer is the most common malignancy in women. Despite the prolongation of survival over the years, the same success has not been achieved in the young subgroup of patients., It is reported that 89.5% of young breast cancer patients presented with a palpable mass at the time of diagnosis. Similarly, in our study 62.9% of patients had T2 or higher T-stage at diagnosis. Breast cancer screening which enables early diagnosis is not routinely incorporated to screening programs of young (<40) patients, except for specific defined conditions such as being a mutation carrier of breast cancer susceptibility genes that leads to advanced disease stage at diagnosis.
Although the breast cancer incidence rates have been stable in high-income countries during the past decade, the same is not true for low-to-middle income countries. In fact, the rise in breast cancer incidence is specifically occurring in the young- and very young-aged populations. In countries located in the Middle East and Mediterranean regions, the incidence of breast cancer in patients under 40 years of age are reported to be between 11% and 23%.
The same pattern of high incidence of young breast cancer patients also holds true for other non-Westernized countries located in South America and Sub-Saharan Africa.,
Early menarche age is associated with an increased risk of breast cancer related to prolonged estrogen exposure. Median menarche age was 13 years in our patients which is similar to the other studies in the literature., Sidoni et al. showed menarche age was 1 year earlier in patients with breast cancer under 40 years old than above 60 years old. Nulliparity is shown to be associated with an increased risk of breast cancer compared to par women (relative risk 1.2–1.7). In our study, only 10.2% of the patients were nulliparous. In European studies analyzing young breast cancer patients, nulliparity rates were higher.,
When the marital status of our patients was questioned, 80.6% were married, 9.7% were single, and 9.7% were widows. All the widows divorced after they received breast cancer diagnosis. It was also remarkable that 8 of our 12 widowed patients were aged <35 years. These observations indicate that pretreatment socio-psychological support should be one of the most important parts of interdisciplinary treatment in young breast cancer cases, and family of the affected patients should be within the scope of supportive programs.
Family history of cancer is an issue that must be questioned, especially in the young-aged breast cancer group, which is a strong risk factor. Several gene mutations other than BRCA genes are also involved in increased risk of development of breast cancer at young age, such as TP53. In our study, 61.4% of the patients in the whole group had a family history of any cancer, while 37% of our patients had a history of breast and/or ovarian cancer. In the literature, the findings are similar with us and the EUSOMA concluded that breast cancer in young women is associated with a positive family history and gene mutations more frequently than in older women.,,
Many studies have shown that breast cancer in young people has more aggressive biologic features than cancer in advanced age such as higher grade, rapid proliferation rate, ER, PR negativity, larger tumor diameter, increased rate of lymphovascular invasion, and more regional lymph node involvement., In our study, 43.2% of the patients had Grade 3 and 44.3% had Grade 2 breast cancer. Most of the studies in the literature reported that the rate of high-grade tumors was higher in younger patients similarly to our findings.,,,,
Luminal A was the least common subtype composing just 16.8% of the study population. This rate is significantly lower when compared to older population where the expected rate of luminal A cancer is 40%. This rate is similar to many of the reported findings in the literature., In contrast, we found the rate of luminal B subtype of breast cancer higher compared to other studies from developed nations., This finding is in line with other studies from developing countries, reporting increased incidence of luminal B breast cancer in the younger populations.
In our study, the rate of triple-negative patients was 15.3%. This rate was 21% in Collins et al.'s study and 38% in Morrison et al.'s study., Özmen's study was similar to ours and was 17%. These findings showed us that triple-negative ratio in young breast cancer patients in our country is lower than Western Europe and America.,, A study from China which is evaluated young breast cancer patients under 40 years old showed that triple-negative ratio was similar with our findings and was 16.7%. In accordance with these findings, another study from Taiwan showed us that hormone-positive subtypes were higher in younger patients (<35 years) from older counterparts (>50 years). The exact mechanism behind relatively higher incidence of hormone receptor-positive breast cancer compared to triple-negative in developing nations compared to Westernized societies is still not clearly understood. Increased dietary caloric intake, reduced childbearing rate, and high exposure to environmental pollutants are among the several factors which are hypothesized to be responsible for this phenomenon.
Young age is one of the factors that increase the risk of local recurrence in breast cancer patients. In our study, 3.8% of the patients recurred locoregionally after primary treatment, while 24.6% of the patients relapsed with distant metastases totaling an overall recurrence rate of 28.4%. In a large study conducted by Han et al. on 9985 patients with breast cancer, under the age of 50, the OS data were compared among age groups. Groups were defined as: <30, 30–34, 35–39 and 40–50 years old. In patients aged <35 years, the risk of death rose by 5% for every 1-year reduction in age, whereas there was no significant change in death risk with age in patients aged 35–50 years. The authors stated that the age of 35 should be the threshold value when defining young patients in breast cancer. In another study by Wang et al., 483 breast cancer patients under 35 years were compared with older patients. In the young group, locoregional relapse rate was 8.9% and distant metastases were seen in 18.8%, which are in line with our findings. It is hypothesized that intensive molecular profiling of breast cancer tumors developing in the very young patient subset may delineate the differences between tumors occurring in different age groups with similar histological characteristics.
The number of patients who underwent amenorrhea after CT was 17.5% (n = 24). However, although the study group consisted from young female individuals, only 3.3% (n = 5) of patients gave birth in the posttreatment period. Breast cancer patients have lower pregnancy rates compared to many of the other young tumor survivors. It can be hypothesized that the remaining ovarian reserve is relatively high after completion of CT since menstrual cycles returned in 113 (82.5%) of our patients. However, given the fact that correlation between menstruation and fertility is lost after receiving CT, the declining quality of the remaining eggs in the ovaries could be a plausible explanation. The low rate of having children may mean that we should take more aggressive fertility prevention approaches before and during treatment. In order to improve further young adult cancer patient's chances of subsequent parenthood, multidisciplinary counseling should focus on not only the cancer treatment but also the effects on future fertility.
Our study has several limitations. First, the sample size was small to find differences between groups. In addition, the fact that some of the parameters we compared, such as grade and Ki-67, were dependent on pathologist view, and also, no single pathology physician had evaluated the specimens. These could be considered as possible causes of this similarity.
Another limitation of our study was that we have indicated the number of dissected lymph nodes to reveal the axillary approach of our clinic on breast surgery. However, we did not follow surgical complications, especially seroma. Seroma formation, an abnormal collection of fluid in the axilla's dead space, is described in the literature with a wide range of incidence (3%–85%)., It causes significant morbidity and discomfort. If we also indicated the frequency of seroma in our patients, our study would be more valuable in the safe management of the axilla in breast cancer.
As a result, we report that young (<40 years) breast cancer patients showed more aggressive biological features compared to the general population. It was observed that the group of very young breast cancer patients (<35) developed significantly more metastases compared to their older counterparts.
| > Conclusion|| |
We recommend for the development of a more vigorous decision-making and age-adjusted posttreatment follow-up modalities for the management of young breast cancer patients. Furthermore, formation of multidisciplinary teams for dealing with cancer survivorship issues such as fertility and marital stability should be encouraged.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]