Evolutionary Profil of Triple-Negative Breast Cancer and Influence of Histopronostic Factors: Experience of Oncology Department Chu Ibn Rochd Casablanca

Triple-negative breast cancer (TNBC) is a subgroup of breast cancer with hormone receptor and Her2 overexpression absence, accounting for 15%–20% of all breast cancers. Its unpredictable evolution, poor treatment response, and highly invasive nature warrant research interest. The main objective of this study is to assess the evolution of triple-negative breast cancer as a role for histopronostic factors. We present the evolutionary profile of triple-negative breast cancer in the role of histopronostic factors using data from a four-year retrospective study of cases of triple-negative breast cancer collected in the oncology-radiotherapy department at Chu Ibn Rochd Casablanca between January 2015 and December 2019. 232 patients were included, regardless of disease stage. The mean age was 49.54 ± 11.21 years. In 68% of cases, the disease was localized. All metastatic patients (32%) died, with a median survival of 15 months. We analyzed the evolution of triple-negative breast cancer in localized disease as a role for age, tumor size, histological type, SBR grade, lymph node invasion, and vascular invasion, with a median follow-up of 24 months (2 years). In 158 patients in our series with localized disease, local or locoregional recurrence was noted in 16% of cases, metastatic relapse in 10%, and 30% of cases were still in complete remission. Patients aged between 40 and 50 had a higher rate of local and locoregional recurrence. Patients with tumors between 2 and 6 cm in size had a high rate of metastasis and death. Grade SBR III is generally marked by a poor prognosis, with 39 patients having local or locoregional recurrence, 41 patients having metastases, and 15 patients having died. In our series, the greater the lymph node and vascular invasion, the poorer the prognosis, with a higher risk of recurrence and metastasis. These results support the role of early screening, especially for at-risk patients, adequate therapeutic management, and active surveillance of patients with triple-negative breast cancer. New research has shown the effectiveness of immune checkpoint inhibitors and anti-parp in treating advanced triple-negative breast cancer (TNBC), with encouraging findings indicating their potential benefit. Clinical studies including anatomical pathologists, oncologists, and fundamental researchers must be conducted globally to achieve this. Clinical studies involving pathologists, oncologists, and basic researchers are needed worldwide to define new therapeutic strategies for the management of this type of aggressive breast cancer.

Introduction

Breast cancer is now the most often diagnosed cancer in the world. This frequency is significantly connected with human growth, with a sharp increase in instances in parts of the world now undergoing economic transition. Survival, on the other hand, is far more difficult in less developed areas. A variety of reasons, including delayed diagnosis and a lack of access to appropriate therapies, explain the discrepancies in global survival rates.

WHO created the Global Breast Cancer Initiative to address this pressing global health issue. It will describe three pillars for increasing global survival rates: health promotion, prompt diagnosis, and comprehensive treatment and supporting care [1]. Treatment techniques differ depending on the molecular subtype. Management is interdisciplinary and includes both locoregional (surgery and radiation) and systemic treatment [2].

Breast cancer is the most common cancer in Morocco, accounting for 22.5% of all cancer cases of both sexes. Its prevalence has grown significantly, with women accounting for 38.1% of cases, making it the most frequent cancer among Moroccan women [3]. It is unique in that it mostly affects young women, and its steadily growing prevalence poses a serious public health issue [4].

TNBC accounts for 15%–20% of all breast cancers and is of special interest for study because of its unpredictable progression due to poor response to therapy and its highly invasive nature. It now has the worst prognosis of any breast cancer subtype, with a significant incidence of metastases and increased morbidity and death within 5 years after diagnosis [5], [6]. TNBC is primarily controlled by standard chemotherapy-type treatment, which frequently results in recurrence due to the lack of particular therapeutic choices [7].

Our research aims to provide insight into the prognostic variables that influence the evolutionary character of triple-negative breast cancer.

Study Outline

1. 1) Recruitment: The study took place in the oncology-radiotherapy department (P40) of the Chu Ibn Rochd in Casablanca.
2. 2) Study Population: We conducted a retrospective study concerning cases of breast cancer (Triple Negative), followed by the oncology-radiotherapy department (P40) of Chu Ibn Rochd of Casablanca between January 2015 and December 2019. Inclusion Criteria i) Patients with histologically confirmed localized metastatic breast cancer. ii) Hormone receptor-negative: PR and ER. iii) HER 2 is not expressed. Exclusion Criteria i) Patients with incomplete histological studies. ii) Patients with incomplete medical records.

Methods

We report, through the data of a retrospective study spread over a period of 4 years concerning triple-negative breast cancer cases, collected in the oncology-radiotherapy department at Chu Ibn Rochd in Casablanca between January 2015 and December 2019, the evolutionary profile of triple-negative breast cancer with the role of histopronostic factors.

Results

Epidemiologic Data

Age: The mean age of our patients was 49.54 ± 11.21 years, with a minimum age of 27 years and a maximum age of 85 years, as shown in Fig. 1.

Fig. 1. Distribution by age.

Family history of cancer: Of the 232 patients, 41 (18%) had a family history of breast cancer, distributed as shown in Figs. 2 and 3: 1^st degree, 18 cases; 2^nd degree, 23 cases. 191 of the cases studied had no family history of cancer, corresponding to 82% of cases.

Fig. 2. Family history of cancer.

Fig. 3. Family history of breast cancer.

History of the Disease

Discovery circumstances: The most frequent reason for consultation in this series was breast nodule in 191 cases i.e., 86%, followed by mastodynia in 18 cases i.e., 8%., as shown in Fig. 4.

Fig. 4. Discovery circumstances.

Delay time to diagnosis: As shown in Fig. 5, the interval between the beginning of symptoms and positive diagnosis ranged from 2 to 24 months, with an average of 7 months. Early diagnosis (less than 3 months) was observed in 50 patients (22%), while late diagnosis (more than 3 months) was observed in 175 patients (75%), time to diagnosis was unknown in 3% of cases.

Fig. 5. Distribution of patients by time to diagnosis.

Clinical Appearance

Tumor location: As shown in Fig. 6, the left breast was the most affected side in 122 patients, i.e., 53% of all cases, whereas the right breast was affected in 110 patients, i.e., 47% of cases, with a clear predominance of the SEQ with a frequency of 58%, followed by the SIQ with a rate of 17%, IEQ with 6%, and the IIQ with 4%, as shown in Fig. 7.

Fig. 6. Distribution of breast nodule location.

Fig. 7. Distribution of breast nodule location.

Tumor size: The size of the tumor in our series ranged from 0.8 cm to 9 cm, with a mean average of 4.17 ± 2 cm, as shown in Fig. 8.

Fig. 8. Distribution of patients according to clinical tumor size.

Lymph node involvement: As shown in Fig. 9, At the time of diagnosis, 93 patients in our series (40%) had lymph node involvement.

Fig. 9. Distribution of patients according to the presence of adenopathy.

Paraclinical Investigation

Ultrasound/Mammography: All patients in our series, as shown in Fig. 10, underwent combined ultrasound and mammography, and mammographic abnormalities were classified according to ACR (American College of Radiology), from BIRADS 0 to BIRADS 5, with BIRADS 4 being found in 38% of cases.

Fig. 10. BIRADS ACR classification.

Anatomopathological exam:

1. Histological diagnosis: Histological confirmation was obtained in all patients as described below: 1.1. Microbiopsy: performed in all 52 patients, i.e., 22%. 1.2. Extemporaneous examination: 11 patients, whose micro-biopsy was inconclusive, benefited from an extemporaneous examination i.e., 5%. 1.3. Anatomopathological examination of the surgical specimen was carried out in 169 patients, i.e., 73%.
2. Histological type: As shown in Fig. 11, Infiltrating carcinoma type NST (No Special Type) was the most common histological type in our series with 194 cases (84%), followed by infiltrating lobular carcinoma with 3%.

Fig. 11. Histological type.

SBR Grade: As shown in Fig. 12, the breast cancers diagnosed were graded according to the Scarff-Bloom-Richardson histopronostic grading. In our series, SBR grade III predominated in 149 patients, SBR grade II in 80, and SBR grade I in 3.

Fig. 12. SBR grade distribution.

Vascular embolus: As shown in Fig. 13, Vascular embolus was found in 123 patients, i.e., 53% of all cases, and absent in 109 patients, i.e., 47% of cases.

Fig. 13. Distribution according to the presence of a vascular embolus.

Extension Investigation

CT-PAT: As shown in Fig. 14, Thoracoabdomino-pelvic CT scans were performed on all patients in our series and showed liver and lung metastases for 74 patients (32%).

Fig. 14. Distribution of patients according to the presence of metastases on CAT scan.

Bone Scan: As shown in Fig. 15, bone scan showed bone metastases in 19 patients (8%), while 213 patients (82%) had no lesions.

Fig. 15. Distribution of patients according to the presence/ or not of bone metastases.

Pet-SCAN: It was performed in 14 patients, i.e., 6% of all cases studied. The distribution of metastases was as shown in Fig. 16.

Fig. 16. Results of extension workup.

BRAIN SCAN: It was performed in 15 patients and showed brain metastases in 13 patients.

Biology: CA15-3 assay was performed in all patients, the mean level in our series being 29.3 U/ml.

Results of extension evaluation:

TNM staging: At the end of this workup, all patients were classified according to the TNM classification of the 8th edition of 2018, as shown in Table I.

Table I. TNM Classification

Stade	Number of cases	Percentage
I	23	10%
IIA	58	25%
IIB	26	11%
IIIA	18	8%
IIIB	21	9%
IIIC	12	5%
IV	74	32%

Treatment

Localized disease:

Neoadjuvant chemotherapy:

Neoadjuvant chemotherapy was adopted first in 46 patients in our series with localized disease (20%), those with tumor size >2 cm or lymph node involvement. The number of courses varied from 6 to 8. The most commonly used protocol was the sequential anthracycline-taxane regimen, as shown in Fig. 17.

Fig. 17. Distribution of patients treated for localized breast cancer, by use or not of neoadjuvant chemotherapy.

Surgery: As shown in Fig. 18, patey surgery was adopted in 120 patients (52%), while conservative surgery, lumpectomy, and axillary lymph node curage, were performed on 94 patients (40%).

Fig. 18. Distribution of patients by type of surgery.

Adjuvant chemotherapy: In our series of patients with localized disease, 144 (62%) received adjuvant chemotherapy in the presence of anatomopathological risk factors such as pT >5 mm or N+. Several protocols were used, with sequential chemotherapy predominating. The number of courses varied between 4 and 8 sessions.

Post-adjuvant chemotherapy: In the absence of a complete anatomopathological response (PCR), capecitabine-based chemotherapy was indicated for 6 months in 33 cases, i.e., 14% of patients in our series.

Radiotherapy: As shown in Fig. 19, 212 patients (92%) underwent radiotherapy after surgery.

Fig. 19. Distribution of patients according to adjuvant radiotherapy use.

Early metastatic disease:

74 patients in our series had metastatic triple-negative breast cancer, with treatment based mainly on palliative chemotherapy.

Palliative chemotherapy: In all cases, Anthracyclines (AC60 and EC100) were used as first-line therapy. For 35 patients, Taxanes with or without Carboplatin were used as 2nd-line therapy.

Evolution

At 34 months follow-up, the results of our work are as detailed in Table II.

Table II. Evolution of Patients with Localized Disease

Evolution	Incidence	%
Local LR recurrence	37	16%
Metastatic recurrence	29	13%
Local or LR ou metastatic recurrence	23	10%

Localized disease: For 158 patients in our series with localized disease, we note that 69 patients are still under surveillance, i.e., 30% of cases.

Metastatic disease: After a follow-up of 34 months of 74 patients with metastatic disease, we, unfortunately, note the death of all patients, with an average of 15 months, the results are shown in Fig. 20.

Fig. 20. Distribution of patients by number of deaths after the follow-up period.

Evolution of Localized Disease According to Histopronostic Factors

We analyzed the evolution of triple-negative breast cancer in localized disease according to age, tumor size, histological type, grade, lymph node invasion, and vascular invasion, with a median follow-up of 24 months (2 years).

According to age: In our series, patients aged between 40 and 54 years had a higher rate of local and locoregional recurrence than other age groups, as shown in Fig. 21.

Fig. 21. Distribution of patient evolution according to age.

According to tumor size: The evolution of patients with a tumor size between 2 and 6 cm was marked by a high rate of local and locoregional recurrence, whereas local and loco-regional recurrences, whereas tumor size greater than 6 cm were marked by a higher rate of metastases and death, as shown in Fig. 22.

Fig. 22. Evolution according to tumor size.

According to histological type: As shown in Fig. 23, the evolution of patients with invasive NOS carcinoma was marked by a higher rate of local recurrence and metastases.

Fig. 23. Evolution of patients according to histological type.

According to SBR grade: As shown in Fig. 24, SBR grade III is generally marked by a poor evolution, 39 patients had local or locoregional recurrence.

Fig. 24. Distribution of patient outcome by SBR grade.

According to lymph node involvement: As shown in Fig. 25, the greater the lymph node involvement, the worse the prognosis.

Fig. 25. Progression of patients according to lymph node involvement.

According to vascular invasion: As shown in Fig. 26, the greater the degree of vascular invasion, the poorer the prognosis, with a higher rate of recurrence and metastases.

Fig. 26. Evolution of patients according to vascular invasion.

Discussion

Triple-negative breast cancer is distinguished by no estrogen and progesterone receptor expression, as well as the lack of Her2 gene amplification, making him not susceptible to endocrine therapy or HER2 treatment [8]. It represents 15%–20% of all new cases of breast cancer and has the poorest prognosis [9].

The median age of diagnosis of triple-negative breast cancer according to an American study of 876 patients carried out in 2019 is 49 years [10], which is consistent with the findings of our investigation.

A family history of breast cancer is frequently related to triple-negative breast cancer. A study of triple-negative breast cancer patients by the American Society of Oncology discovered that 34% of patients with family history information had at least one relative with breast cancer, and 4% had a relative with ovarian cancer [11]. In our study, 18% of patients had a family history of cancer.

The most prevalent circumstance of discovery, in 90% of cases of our series, was the palpation of a breast nodule, this result is consistent with literature data [12]. In 61% of instances, the nodule was found in the upper external quadrant, whereas 47% were found in the posterior third of the breast [13]. The upper exterior quadrant was the most afflicted in 58% of patients in our study.

Concerning time to diagnosis, triple-negative breast cancers (TNBC) are more often diagnosed at the stage of a clinically detectable tumor than at the stage of a mammographic finding with a high false-negative rate during complementary examinations, thus increasing the time to diagnosis [14]. In our series, the delay was longer than 3 months in 80% of instances, which is consistent with the findings of another study, which found a delay of more than 3 months in 57% of cases [15].

TNBC appears on mammography as a mass with confined margins in 20%–24% of cases and lacks the typical worrisome mammographic characteristics of breast cancer, such as uneven mass shape, speculative margins, and concomitant suspicious calcifications [16], [17]. In a study by Seifeddine Ben Hammouda et al. concerning women with triple-negative breast cancer, mammographic abnormalities were classified as ACR 4 in 11 cases, ACR 5 in 11 cases, and ACR 3 in 2 cases [11]. In our study, BIRADS 4 was the most common classification, accounting for 38% of cases, followed by BIRADS 5 in 35% of cases.

Triple-negative cancer is associated with a large tumor at the time of diagnosis, according to a study by Thike AA et al., in 653 women with triple-negative breast cancer, 70% of patients had a tumor larger than 2 cm [18]. In our study, the mean tumor size was 4.17 ± 2 cm.

For pathological examination, the most frequent histological type in patients with triple-negative breast cancer (TNBC) is infiltrating ductal carcinoma (IDC) [19], which is in line with the results of our study. A study conducted by Derkaoui et al. [20], which included 279 patients with breast cancer, 49 of whom had triple negative breast cancer, showed a predominance of grade III, in 40.4%. As in our study, which showed a predominance of SBR grade III in 64% of cases. A pre-chemotherapy extension work-up using CTAP, bone scan, and CA15.3 revealed stage I in 10% and stage 4 in 32% of our patients. In contrast, Chinese research [21], conducted in 2020 found stage I in 42.1% of cases and stage IV in 0%. Such results can be explained by the tardiness of diagnosis in our country.

Despite the poor prognosis of triple-negative breast cancer, its lower overall survival, and the high chance of recurrence, TNBC appears to respond to chemotherapy better than other kinds of breast cancer [22]. A meta-analysis of 34 research published in the United States in 2020 reinforces the benefit of neoadjuvant chemotherapy, emphasizing the statistically prolonged overall survival and event-free survival associated with adjuvant therapy in patients with early-stage TNBC after neoadjuvant therapy [23]. Another study found that almost one-third of triple-negative breast cancer patients who received neoadjuvant chemotherapy had a higher chance of achieving full remission (PCr) compared to various breast cancer subtypes [24]. In our study, neoadjuvant chemotherapy was adopted in 46 patients, i.e., 20% of cases. Surgery is crucial in the treatment of triple-negative breast cancer (TNBC). While the aggressive nature of TNBC used to need a severe surgical procedure, such as mastectomy, current research has shown that conservative therapy has no effect on the likelihood of local recurrence [25], [26]. A randomized experiment demonstrates that the evolutionary profile of TNBC is the same regardless of the type of surgery used [27]. PATEY-type surgery was used in 120 individuals in our research, while conservative surgery was used in 94 patients.

Despite reaching pCR remains the aim of neoadjuvant treatment, proper treatment of individuals who do not accomplish this goal is crucial since these patients have a six to nine times higher recurrence [28]. CREATE-X study showed that post-neoadjuvant capecitabine-based chemotherapy improved DFS and OS in patients with residual disease following neoadjuvant chemotherapy [29].

The combination of early breast-conserving surgery and whole-breast radiation has lowered the local recurrence rate from 10% to roughly 2%. This advancement is aided not just by breakthroughs in radiation, but also by earlier diagnosis and improved pathology assessment, as well as more effective prognostic-based systematic therapy [30]. Abdulkarim et al. found that the recurrence-free survival rates of breast-conserving surgery combined with radiotherapy, modified radical mastectomy without adjuvant radiotherapy, and modified radical mastectomy with adjuvant radiotherapy were 94%, 85%, and 87%, respectively, with a mean follow-up of 7.2 years. Postoperative radiation can reduce the incidence of local recurrence in triple-negative breast cancer, underscoring the relevance of radiotherapy in TNBC local management [27]. A 2019 study validates the last point and underscores the beneficial impact of radiation after surgery on survival [31]. In our series, 212 patients (92% of cases) underwent postoperative radiotherapy.

Triple-negative breast cancer is characterized by a high level of severity at the time of diagnosis. The majority of cancers are grade SBR III, and are characterized by a large tumor, rapid development and frequent association with ganglionic and vascular invasion, and the presence of metastases [32]. This severity in the moment of diagnosis gives it a particular evolutionary profile. According to research that studied the progression of 1,601 breast cancer patients in order to determine the evolutionary nature of triple-negative breast cancer compared to other types: the time to recurrence is shorter in TNBC patients (2.8 years vs. 4.2 years), the death rate is much higher in TNBC patients (42.2% vs. only 28% in other types of cancer), and the risk of relapse in triple-negative cancer increases significantly from the time of diagnosis, peaking at 2–3 years and then declining [33]. Our findings suggest that local or locoregional recurrence occurs in 16% of patients and metastatic relapse occurs in 13% of cases.

The evolutionary profile of the localized disease in the triple-negative breast cancer has been analyzed in the literature as a role for a number of prognostic factors, including age, tumor size, histological type, SBR grade, and lymph node status.

The impact of age on the prognosis of triple-negative breast cancer is still debatable; some studies link aging to shorter survival due to delayed detection and related comorbidities, while others link younger individuals with rapid disease progression [34]. According to research by Radosa et al. [35], there was no discernible difference in local recurrence (LR) or disease-free survival (DFS) between patients <40 and ≥40 years of age. In our series, patients aged between 40 and 54 years had a higher rate of local and locoregional recurrence than other age groups.

Tumor size is a significant prognostic factor in triple-negative breast cancer, the results of our study are consistent with those reported in the literature because patients with tumors larger than 2 cm were identified to have a worse outcome, as demonstrated in the study done by Li X et al. in triple-negative breast cancer, which showed that larger tumors were associated with poorer survival [36].

Numerous previous studies have examined the prognostic impact of histological type on breast cancer progression, with conflicting results. In a study carried out by Zhao [37], for (RH-) (HER2-), invasive lobular carcinoma and invasive ductal carcinoma showed better OS and DFS compared with mixed ductal and lobular carcinoma by multivariate analysis. In our study, the histological type most marked by an unfavorable evolution was invasive carcinoma (NOS), these results can be explained by the fact that this histological type was the most represented in our series with 84% of cases.

Triple-negative breast cancer is often associated with a high SBR grade, which makes it a very important prognostic marker associated with an unfavorable evolution [38]. According to our research, the SBR III stage saw a negative evolution.

Compared to individuals without lymph node involvement, the risk of mortality for those with triple-negative breast cancer is doubled by 5 in cases with lymph node involvement [39]. The presence of vascular invasion is also associated with reduced overall survival [40]. Our study’s findings are in line with those published in the literature: the prognosis is worse the more lymph nodes are damaged and the more vascular invasion is present.

Conclusion

A breast cancer subtype with a poor prognosis known as triple-negative breast cancer is immunohistochemically identified by the lack of estrogen, progesterone, and HER 2-receptor expression. With a significant probability of local and metastatic recurrence, triple-negative breast cancer presently has the worst prognosis of all breast cancer subtypes. Although these patients frequently respond to neoadjuvant chemotherapy, their prognosis is still dismal, hence it is critical to use more aggressive tactics to increase survival. Due to the surprising degree of heterogeneity in triple-negative breast cancer, novel therapeutic targets have been found, including BRCA 1 and BRCA 2 mutations, which are now included in the CSTN’s toolkit of treatments. On the other hand, research has shown the effectiveness of immune checkpoint inhibitors in treating advanced triple-negative breast cancer (TNBC), with encouraging findings indicating their potential benefit. Clinical studies including anatomical pathologists, oncologists, and fundamental researchers must be conducted globally to achieve this.