Pattern of Breast Cancer in Young Females in Minia Governorate.

Introduction

Breast cancer (BC) is the most common cancer in women. Although the incidence of BC is age-dependent, a constant increase in BC diagnoses in women younger than 40 years has been recently reported in several countries, with approximately 11% of new cases diagnosed in women who are 45 years of age or younger.  A variety of risk factors for breast cancer have been well-established by epidemiologic studies including race, ethnicity, family history of cancer, and genetic traits, as well as modifiable exposures such as increased alcohol consumption, physical inactivity, exogenous hormones, and certain female reproductive factors. Younger age at menarche, parity, and older age at first full-term pregnancy may influence breast cancer risk through long-term effects on sex hormone levels or by other biological mechanisms.

Different types of breast cancer diagnostic examinations are also available, such as mam-mography, breast MRI, biopsy, ultrasound and molecular imaging appropriate workup of physical symptoms is essential in these patients. ⁽¹⁾

Breast cancer can be broadly categorized on the basis of histological outcome into in situ carcinoma and invasive carcinoma. Breast carcinoma in situ is further sub-classified as either ductal (DCIS; more common) or lobular (LCIS; less common). Among the invasive carcinomas IDC is the most common subtype accounting for 70–80% of all invasive lesions.

IDC is further sub-classified as well-differentiated (grade 1), moderately differen-tiated (grade 2) or poorly differentiated (grade 3) based on the levels of nuclear pleomorphism, glandular/tubule formation and mitotic index.

Breast cancers are then classified with respect to the presence or absence of these receptors as Luminal A (ER and PR positive, and HER2 negative); Luminal B (ER and/or PR positive, HER2 negative and high KI67); HER2-enriched (ER and PR negative, and HER2 positive) and Basal Like (Triple negative breast cancer- ER, PR and HER2 negative). ⁽²⁾

The therapeutic approaches that are employed for breast cancer management include cytoreductive surgery, radiation treatment, targeted endocrine/molecular therapy and chemotherapy Due to the heterogeneity of the disease the treatment protocol requires rationalized therapy in individual cases according to the characterization and stage of the disease.

There are two major types of surgical procedures enabling the removal of breast cancerous tissues and those include (1) breast-conserving surgery (BCS) and (2) mastectomy. BCS-also called partial/segmental mastectomy, lumpectomy, wide local excision, or quadrant-ectomy the removal of affected lymph nodes involves sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND).

Chemotherapy is a systemic treatment of BC and might be either neoadjuvant or adjuvant. Choosing the most appropriate one is individualized according to the characteristics of the breast tumor; chemotherapy might also be used in the secondary breast cancer. Neoadjuvant chemotherapy is used for locally advanced BC, inflammatory breast cancers, for downstaging large tumors to allow BCS or in small tumors with worse prognostics molecular subtypes (HER2 or TNBC) which can help to identify prognostics and predictive factors of response. ⁽³⁾

Radiotherapy is local treatment of BC, typically provided after surgery and/or chemotherapy. It is performed to ensure that all of the cancerous cells remain destroyed, minimizing the possibility of breast cancer recurrence. Further, radiation therapy is favorable in the case of metastatic or unresectable breast cancer.

Endocrinal therapy might be used either as a neoadjuvant or adjuvant therapy in patients with hormonal positive  Breast Cancer; it is effective in cases of breast cancer recurrence or metastasis Drugs that block ERs while treatments that aim to lower the estrogen levels include aromatase inhibitors (AIs) .In the case of pre-menopausal women, ovarian suppression induced by oophorectomy, luteinizing hormone-releasing hormone analogs, or several chemotherapy drugs, are also effective in lowering estrogen levels^.(4)

Biological therapy (targeted therapy) can be provided at every stage of breast therapy– before surgery as neoadjuvant therapy or after surgery as adjuvant therapy. Biological therapy is quite common in HER2-positive breast cancer patients; major drugs include trastuzumab, pertuzumab, trastuzumab derux-tecan, lapatinib, and neratinib.

Among breast cancer survivors, 32–93% of women report sexual problems and 27% to 88% report body image concerns. For women of reproductive age, treatments for breast cancer may also negatively impact fertility. Breast cancer treatment-related changes in sexual and reproductive health are associated with significant distress and often negatively impact women’s emotional well-being, relationships, sense of self, and overall quality of life^.(5)

Aim of the study

This study will be carried out to determine the pattern of breast cancer in young females in our community regarding hormonal manipulation, age of marriage, consanguinity, site, pathology, grade, Tumor size, lymph node status,  mole-cular classification ( ER, PR, HER2 neu positive, Triple negative , basal like, ), KI67 and reflection on overall survival from year 2017 to 2021.

Patients and methods

The  data for patients with primary breast cancer who were diagnosed by pathologically proven breast cancer below age of 40 years collecting from female cases from Minia university hospital and Minia oncology center from period 2017 to 2021. TNM staging system (according to American Joint Committee on Cancer AJCC 2017) was used for staging. Immunohistochemistry was used for molecular classification.

Inclusion criteria:

Female ageed below 40y, with biopsy-proven invasive lobular or ductal carcinoma.

1. Staging by (TNM staging system).
2. Hormonal manipulation (Contraceptive usage, ovulation induction).
3. Time of menarche.
4. Family history.
5. consanguinity
6. Molecular classification.

Ethical consideration:

An ethical approval was taken from Research Ethics Committee of faculty of Medicine, Minia University and Minia oncology center. 

Statistical analysis:

Data were collected, revised, coded and entered to the Statistical Package for Social Science (IBM SPSS) version 20. The qualitative data were presented as number and percentages while quantitative data were presented as mean, standard deviations and ranges for normally distributed data. Cox regression analysis was used for prediction of mortality

The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the p-value was considered significant as the following:

P> 0.05 = non significant (NS)

P < 0.05 = significant (S)

P < 0.001 = highly significant (HS).

Results

A total of 279 cases were included. In this study, there were 34 patients were Age < 30 years (12.2%) and 245 were in age between 30 – 40 years (87.8%) , The median age of enrolled

patients was 34.6±4.5 years (range 22–40 years). Sixty sex (23.7%) patients had positive family history of breast cancer, and 160 patients (57.3%) used hormonal contraceptive, patients were 225 (91.4%) with no consanguinity. There were 227 (81.4%) patients with negative ovulation induction. Time of first Menarche < 13 years was recorded in 32.3% of patients.

The majority of patients has invasive duct carcinoma (254 cases  (91%) ) while invasive lobular carcinoma ILC represent only  14 cases  (5.0%), other pathology like DCIS , LCIS , phylloid tumor represent minority of cases and 

TNM staging revealed that 230 (82.4%) of patients with Grade II, 128 (45.9%) with T2 and 95 (34.1%) with N1 status.

Molecular classification of these cases was luminal A in 98 case (35.7%), luminal B 85 case (30.5%), HER2 positive 47case (16.8%)  and Triple negative patients 49 case (17.6%).

161 patients (57,7%) were still alive, 118 patients (42.3%)  dead . Our results showed that, OAS range was (6-87months) and mean ± SD (43.5 ± 17.4).

Cox regression analysis for prediction of mortality revealed that ki67 level was a significant predictor of   the overall survival with HR (95% CI); 1.64 (1.135-2.375)

There was association of primary tumor stage T and the prevalence of metastasis to lymph  nodes.

Discussion

Breast cancer is considered as a heterogeneous condition and so requires evaluation of as many clinical and pathological features as possible to allow for best prediction of survival.

Our results showed that, there were 254(91%) patients with IDC, 14(5.0%) patients with ILC and 11(3.9%) patients with other pathological subgroup.This agreed with a study that aimed to compare the characteristics of breast cancer in a group of young women with a group of postmenopausal women and confirm the higher malignant potential of cancer in the population of young women. They reported that Invasive ductal carcinoma was the most frequent histologic type of tumor. The second most common type was invasive lobular carcinoma ^(6).

The age of the patient is a well-defined prognosis factor for local recurrence. It is well established that patient age greater than 35 or 40 is associated with an increased frequency of local recurrence due to presence of various adverse pathologic features, such as lymph vascular invasion, grade 3 histology, absence of Estrogen Receptor (ER) and Progesterone Receptor (PR), presence of HER2 and presence of extensive intra-ductal component. ⁽⁷⁾

Turkish study  showed the molecular sub-type analysis of the tumors  that 57.7% of the tumors were luminal A (ER and/or PR positive, HER-2 negative, low KI67 ), 20.6% were luminal B (ER and/or PR positive, HER-2 positive, high KI67 ), 9.6% were HER-2 type (ER and PR negative, HER-2 positive) and 12.1% were triple negative which agreed with our study. ⁽⁸⁾

Lymph node involvement has long been recognized as an important prognostic factor in breast cancer. The presence of positive axillary lymph nodes is a predictor of increased risk of local and distant recurrence, directly affecting mortality. The association between lymph node involvement and survival has been previously demonstrated  and it has been shown that overall survival rates are up to 40% lower in node-positive patients compared with node-negative ones ^.(9)

Retrospective cohort study of node-positive stage II and III breast cancer patients diagnosed and treated between 2008 and 2009 at the Brazilian National Cancer Institute the median overall survival times of low-, in­termediate-, and high-risk LNR patients were 55.6, 52.9, and 48.8 months, respectively (p<0.001) ⁽¹⁰⁾

In our study we found lymph node negative were (N0) 70 patients with estimated mean 58.6% and CI (53.9- 63.3). N1 95 patients estimated mean 58.7 and CI (54.3 – 63.1), N2 79 patients estimated mean 57.6 and CI (52, 9- 62, 3) and N3, 35 patients estimated mean 62.8  and CI (56.2 -69.4)

In the current study the impact of molecular classification luminal A 98 cases (35.7%), luminal B 85 cases (30.5%), HER2 positive 47cases (16.8%)  and Triple negative patients 49 cases (17.6%) and that is not statistically significant on overall survival.

There are also studies investigating influence of reproductive factors on tumor characteristics and breast cancer survival in women. An association had been found between early age at menarche and reduced survival. Age at menarche was also shown to be significantly associated with tumor grade and lymph node involvement. ⁽¹¹⁾

Breast cancer survival varies substantially by stage at diagnosis. Pinheiro et al., showed the 5-year relative survival for patients diagnosed during 2012–2018 was >99% for stage I disease, 93% for stage II, 75% for stage III, and 29% for stage IV. Except for stage I, for which survival is similar, Black women have the lowest survival for every stage of diagnosis, with the largest Black–White disparities among those diagnosed with stages III and IV disease. ⁽¹²⁾

And the  5-year overall survival  According to the Iranian study, Ki67 could not be used as an independent prognostic factor for invasive breast cancers. It was also concluded that there is no significant relationship between Ki67 and some prognostic factors such as hormonal receptors and HER2. In addition, no significant difference was observed between Ki67 and 3‑ and 5‑year DFS with 5‑year OS. In our study ki67 level was a significant predictor of   the overall survival with HR (95% CI); 1.64 (1.135-2.375)

There is an association of primary tumor stage T and the prevalence of metastasis to lymph  nodes was statistically significant with p value < 0.001 .