Prognostic factors in triple-negative breast cancer: a retrospective cohort

SUMMARY

OBJECTIVE:

Triple-negative breast cancer (TNBC) is characterized by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression and accounts for 15–20% of all breast cancers. This study aims to analyze prognostic factors related to a reduction in overall survival (OS), disease-free survival (DFS), and risk of mortality and recurrence in TNBC.

METHODS:

This is a retrospective observational cohort study. Medical records of 532 patients with breast cancer diagnosed from 2007 to 2020 were analyzed. Of these patients, 93 (17%) were women with TNBC. Ten medical records were excluded, and the final sample was composed of 83 women with TNBC. OS and DFS were estimated by the Kaplan-Meier model. Univariate analysis (log-rank test) and multivariate analysis (Cox regression) were used to examine prognostic factors related to a statistically significant reduction (p<0.05) in OS and DFS and increased risk of mortality and tumor recurrence.

RESULTS:

Smoking, advanced clinical stage, larger tumor size, angiolymphatic invasion, positive sentinel lymph node, axillary node involvement, higher cancer burden, surgical treatment with mastectomy, and recurrence were related to a significant decrease in OS and/or DFS and increased risk of mortality and/or recurrence in TNBC. The 10-year OS and DFS was around 61 and 65%, respectively.

CONCLUSIONS:

Advanced clinical stage, positive sentinel lymph node, axillary node involvement, surgical treatment with mastectomy, and higher residual cancer burden were related to a significant reduction in OS and DFS and increased risk of mortality and recurrence in TNBC.

KEYWORDS:
Survival analysis; Prognosis; Medical records; Pathological conditions; Anatomical; Triple-negative breast neoplasms

INTRODUCTION

Breast cancer is a heterogeneous disease involving multiple genetic alterations¹. It is classified into molecular subtypes, based on the lack of protein expression of estrogen receptor (ER) and progesterone receptor (PR) and the absence of overexpression of human epidermal growth factor 2 receptor (HER2). Triple-negative (TN) subtype is defined as a breast cancer with negative expression of estrogen/progesterone (ER/PR) hormone receptors and human epidermal growth factor receptor-2 (HER2) (either by immunohistochemistry [IHC; 0–1] or by fluorescent in situ hybridization [FISH negative if 2+ on IHC])². TN cancer tends to be more aggressive than other types of breast cancer. It is also associated with a poor prognosis due to its clinical behavior and lack of molecular targets for cancer therapy. Therefore, chemotherapy remains the primary treatment of choice for patients diagnosed at early or late stages³.

In Brazil, the National Cancer Institute estimated that 66,280 new breast cancer cases occurred in women in 2020. Breast cancer was the leading cause of death from cancer among this population⁴. On the other hand, triple-negative breast cancer (TNBC) accounts for around 15–20% of all breast cancers⁵. This molecular subtype of cancer is most commonly observed in young black and Hispanic women. In addition, it is associated with a higher prevalence of BCRA gene mutations (particularly BRCA1)⁶.

In comparison to other subtypes of breast cancer, survival is shorter and mortality rate is 40% in patients with TNBC within the first 5 years of diagnosis, as shown by epidemiological data. TNBC is a highly invasive tumor, and approximately 46% of patients with TNBC develop distant metastasis. Median survival time after metastasis is only 13.3 months, and the recurrence rate after surgery achieves 25%. Brain and visceral metastases frequently occur. The mortality rate of patients with TNBC within 3 months of recurrence is up to 75%⁷.

In the literature, diverse prognostic factors have been associated with TNBC, including recurrence, lymphovascular invasion, tumor size, lymph node involvement, and Ki-67 expression, among others^8,9. The prognostic value of Ki-67 in TNBC remains controversial, partly due to the lack of agreement on the cutoff point, which is estimated at 10–61%⁹.

Recent studies have also evaluated other prognostic factors. Oshi et al. correlated a high CD8 T-cell score with increased survival rates in patients with TNBC. O'Conor et al. reported that CD44⁺/CD24^- and ALDH1⁺ stem cells are indicators of a poor prognosis, contributing to chemotherapy resistance and metastatic tumors. Furthermore, some ongoing trials currently investigate specific genes or microRNA^10-12.

The current study aimed to analyze prognostic factors related to a reduction in overall survival (OS), disease-free survival (DFS), and risk of mortality and recurrence in TNBC.

METHODS

This is a retrospective observational cohort study. Medical records of 532 patients diagnosed with breast cancer were analyzed. Patients were seen from 2007 to 2020 in a private oncology health care facility in the city of Teresina (PI), Brazil. Of these patients, 93 (17%) were women with TNBC. Ten medical records were excluded: four of patients who had not completed treatment by the end of the follow-up (December 2020) and six with incomplete or missing data. The final sample was composed of 83 women with TNBC.

Data were tabulated using the Microsoft Excel 2010® program. Statistical analysis was conducted in the Stata 14® program. The absolute (n) and relative (%) frequencies of each variable of the study were calculated. OS and DFS were estimated by the Kaplan-Meier method. Univariate (log-rank test) and multivariate (Cox regression) analysis investigated which prognostic factors were related to a statistically significant reduction (p<0.05) in OS and/or DFS and a higher risk of mortality and/or recurrence. To perform Cox regression, the hazard ratios along with their respective 95% confidence intervals (95% CI) were estimated.

In the OS and DFS curves presented, follow-up had occurred between the time of TNBC diagnosis and the time of patient death or tumor recurrence, respectively. The maximum follow-up period was 157 months.

The study complied with all Brazilian principles for ethical research (National Health Council Resolution no. 466/12) and was approved by the Research Ethics Committee of the State University of Piauí, Teresina (PI), Brazil (CAAE: 30154720.0.0000.5209).

RESULTS

Prognostic factors (variables) related to the risk of mortality and/or recurrence and impact on the decrease in OS and/or DFS analyzed by univariate and multivariate analysis in this study were age, number of pregnancies, smoking, alcohol dependence, comorbid conditions (hypertension and diabetes), family history (of breast cancer and other cancers), clinical stage, degree of differentiation, tumor size, angiolymphatic invasion, sentinel lymph node, axillary node involvement, Ki-67, residual cancer burden, surgical treatment, and tumor recurrence.

Smoking, advanced clinical stage, larger tumor size, angiolymphatic invasion, positive sentinel lymph node, axillary node involvement, higher residual cancer burden, surgical treatment with mastectomy, and recurrence were regarded as significant risks (p<0.05) of mortality in TNBC and are associated with decreased OS (Table 1).

Table 1
Prognostic factors, deaths, and overall survival (157 months of follow-up).

Variables		n (%)	Death(s) n (%)	Univariate analysis		Multivariate analysis
				Overall survival n (95%CI)	Log-rank test p-value	RR (95%CI)	Wald's test p-value
Age at diagnosis
	≤59 years	50 (60.2)	7 (14.0)	86.0 (73.2–94.2)	0.930	1.0	0.931
	≤60 years	33 (39.8)	5 (15.2)	84.8 (68.1–94.9)		1.05 (0.33–3.33)
Number of pregnancies
	None	17 (20.5)	2 (11.8)	88.2 (63.6–98.5)	0.358	1.0
	1	13 (15.7)	2 (15.4)	84.6 (54.6–98.1)		1.02 (0.14–7.28)	0.987
	2	22 (26.5)	5 (22.7)	77.3 (54.6–92.2)		2.19 (0.42–11.41)	0.352
	3	19 (22.9)	1 (5.3)	94.7 (74.0–99.9)		0.32 (0.03–3.53)	0.349
	4 and more	12 (14.5)	2 (16.7)	83.3 (51.6–97.9)		1.05 (0.14–7.71)	0.964
Smoking
	No	79 (95.2)	10 (12.7)	87.3 (78.0–93.8)	0.004	1.0	0.015
	Yes	4 (4.8)	2 (50.0)	50.0 (6.8–93.2)		7.28 (1.48–35.80)
Alcohol dependence
	No	78 (94.0)	10 (12.8)	87.2 (77.7–93.7)	0.094	1.0	0.118
	Yes	5 (6.0)	2 (40.0)	60.0 (14.7–94.7)		3.47 (0.73–16.46)
Hypertension
	No	60 (72.3)	7 (11.7)	88.3 (77.4–95.2)	0.517	1.0	0.520
	Yes	23 (27.7)	5 (21.7)	78.3 (56.3–92.5)		1.46 (0.46–4.70)
Diabetes
	No	73 (88.0)	10 (13.7)	86.3 (76.2–93.2)	0.328	1.0	0.341
	Yes	10 (12.0)	2 (20.0)	80.0 (44.4–97.5)		2.11 (0.45–9.81)
Family history (breast cancer)
	No	57 (68.7)	10 (17.5)	82.5 (70.0–91.2)	0.459	1.0	0.467
	Yes	26 (31.3)	2 (7.7)	92.3 (74.9–99.0)		0.56 (0.12–2.62)
Family history (cancers)
	No	42 (50.6)	6 (14.3)	85.7 (71.5–94.6)	0.824	1.0	0.825
	Yes	41 (49.4)	6 (14.6)	85.4 (70.8–94.4)		1.14 (0.36–3.54)
Clinical stage
	IB	25 (30.1)	1 (4.0)	96.0 (79.6–99.9)	0.019	1.0
	IIB	24 (28.9)	2 (8.3)	91.7 (73.0–99.0)		1.74 (0.16–19.49)	0.651
	IIIB	23 (27.7)	5 (21.7)	78.3 (56.3–92.5)		6.63 (0.77–57.31)	0.085
	IIIC and IV	11 (13.3)	4 (36.4)	63.6 (30.8–89.1)		10.67 (1.19–95.66)	0.034
Grade
	G2	45 (54.2)	6 (13.3)	86.7 (73.2–94.9)	0.932	1.0	0.933
	G3	38 (45.8)	6 (15.8)	84.2 (68.7–94.0)		0.95 (0.30–2.98)
Tumor size (cm)
	0–2.5	48 (57.8)	4 (8.3)	91.7 (68.7–94.0)	0.025	1.0	0.036
	>2.5	35 (42.2)	8 (22.9)	77.1 (59.9–89.6)		3.73 (1.09–12.74)
Lymphatic invasion
	No	63 (75.9)	3 (4.8)	95.2 (86.7–99.0)	<0.001	1.0	<0.001
	Yes	20 (24.1)	9 (45.0)	55.0 (31.5–76.9)		17.48 (3.72–82.17)
Vascular invasion
	No	67 (80.7)	5 (7.5)	92.5 (83.4–97.5)	<0.001	1.0	0.001
	Yes	16 (19.3)	7 (47.8)	56.2 (29.9–80.2)		7.59 (2.20–26.18)
Sentinel lymph node
	Negative	63 (75.9)	6 (9.5)	90.5 (80.4–96.4)	0.009	1.0	0.017
	Positive	20 (24.1)	6 (30.0)	70.0 (45.7–88.1)		4.23 (1.29–13.88)
Axillary involvement
	No	45 (54.2)	3 (6.7)	93.3 (81.7–98.6)	0.025	1.0	0.039
	Yes	38 (45.8)	9 (23.7)	76.3 (59.8–88.6)		3.98 (1.07–14.76)
Ki-67 (%)
	≤60	34 (47.0)	4 (10.3)	89.7 (75.8–97.1)	0.232	1.0	0.243
	>60	44 (53.0)	8 (18.2)	81.8 (67.3–91.8)		2.05 (0.61–6.87)
Residual cancer burden
	pCR	42 (50.6)	2 (4.8)	95.2 (83.8–99.4)	<0.001	1.0
	RCB-I and RCB-II	29 (34.9)	2 (6.9)	93.1 (77.2–99.1)		1.99 (0.26–15.08)	0.505
	RCB-III	12 (14.5)	8 (66.7)	33.3 (9.9–65.1)		27.80 (4.74–162.9)	<0.001
Surgical treatment
	Conservative	61 (73.5)	6 (9.8)	90.2 (79.8–96.3)	0.012	1.0	0.020
	Mastectomy	22 (26.5)	6 (27.3)	72.7 (49.8–89.3)		3.93 (1.24–12.4)
Recurrence
	No	65 (78.3)	3 (4.6)	95.4 (87.1–99.0)	<0.001	1.0	0.001
	Yes	18 (21.7)	9 (50.0)	50.0 (26.0–74.0)		15.38 (3.26–72.53)

• RR: relative risk; 95%CI: 95% confidence interval; pCR: pathological complete response; RCB-I: minimal burden (residual disease); RCB-II: moderate burden (residual disease); RCB-III: extensive burden (residual disease). The values highlighted in bold are intended to draw the reader's attention to statistically significant variables

In contrast, advanced clinical stage, positive sentinel lymph node, axillary node involvement, higher residual tumor burden, and surgical treatment with mastectomy were also related to a significant risk (p<0.05) of tumor recurrence in TNBC, presenting a reduction in DFS (Table 2).

Table 2
Prognostic factors, tumor recurrence, and disease-free survival (157 months of follow-up).

Variables		n (%)	Recurrence(s) n (%)	Univariate analysis		Multivariate analysis
				Disease-free survival n (95%CI)	Log-rank test p-value	RR (95%CI)	Wald's test p-value
Age at diagnosis (year)
	Up to 59	50 (60.2)	12 (24.0)	76.0 (61.8–86.9)	0.529	1.0	0.533
	60 or above	33 (39.8)	6 (18.2)	81.8 (64.5–93.0)		0.73 (0.33–3.33)
Number of pregnancies
	None	17 (20.5)	2 (11.8)	88.2 (63.6–98.5)	0.001	1.0
	1	13 (15.7)	5 (38.5)	61.5 (31.6–86.1)		3.44 (0.66–17.77)	0.140
	2	22 (26.5)	9 (40.9)	59.1 (36.4–79.3)		4.88 (1.05–22.67)	0.043
	3 or more	31 (37.3)	2 (6.4)	93.6 (78.6–99.2)		0.47 (0.07–3.34)	0.451
Smoking
	No	79 (95.2)	12 (20.2)	79.8 (69.2–88.0)	0.041	1.0	0.062
	Yes	4 (4.8)	2 (50.0)	50.0 (6.8–93.2)		4.20 (0.93–18.91)
Alcohol dependence
	No	78 (94.0)	16 (20.5)	79.5 (68.8–87.8)	0.350	1.0	0.362
	Yes	5 (6.0)	2 (40.0)	60.0 (14.7–94.7)		1.99 (0.45–8.73)
Hypertension
	No	60 (72.3)	14 (23.3)	76.7 (64.0–86.6)	0.471	1.0	0.476
	Yes	23 (27.7)	4 (17.4)	82.6 (61.2–95.0)		0.67 (0.22–2.03)
Diabetes
	No	73 (88.0)	16 (21.9)	78.1 (66.9–86.9)	0.791	1.0	0.793
	Yes	10 (12.0)	2 (20.0)	80.0 (44.4–97.5)		1.22 (0.28–5.36)
Family history (breast cancer)
	No	57 (68.7)	13 (22.8)	77.2 (64.2–87.3)	0.897	1.0	0.898
	Yes	26 (31.3)	5 (19.2)	80.8 (60.6–93.4)		0.93 (0.33–2.63)
Family history (cancers)
	No	42 (50.6)	9 (21.4)	78.6 (63.2–89.7)	0.930	1.0	0.930
	Yes	41 (49.4)	9 (22.0)	78.0 (62.4–89.4)		1.04 (0.41–2.63)
Clinical stage
	IB	25 (30.1)	1 (4.0)	96.0 (79.6–99.9)	0.017	1.0
	IIB	24 (28.9)	6 (25.0)	75.0 (53.3–90.2)		5.04 (0.61–41.9)	0.134
	IIIB	23 (27.7)	6 (26.1)	73.9 (51.6–89.8)		7.33 (0.88–61.06)	0.065
	IIIC and IV	11 (13.3)	5 (45.4)	54.6 (23.4–83.2)		15.25 (1.78–130.70)	0.013
Grade
	G2	45 (54.2)	10 (22.2)	77.8 (62.9–88.8)	0.633	1.0	0.635
	G3	38 (45.8)	8 (21.0)	79.0 (62.7–90.4)		0.80 (0.31–2.03)
Tumor size (cm)
	0–2.5	48 (57.8)	8 (16.7)	83.3 (69.8–92.5)	0.144	1.0	0.154
	>2.5	35 (42.2)	10 (28.6)	71.4 (53.7–85.4)		1.97 (0.78–5.02)
Lymphatic invasion
	No	63 (75.9)	11 (17.5)	82.5 (70.9–90.9)	0.072	1.0	0.082
	Yes	20 (24.1)	7 (35.0)	65.0 (15.4–59.2)		2.34 (0.90–6.10)
Vascular invasion
	No	67 (80.7)	13 (19.4)	80.6 (69.1–89.2)	0.336	1.0	0.343
	Yes	16 (19.3)	5 (31.2)	68.8 (41.3–89.0)		1.65 (0.58–4.66)
Sentinel lymph node
	Negative	63 (75.9)	10 (15.9)	84.1 (72.7–92.1)	0.008	1.0	0.017
	Positive	20 (24.1)	8 (40.0)	60.0 (36.0–80.9)		3.23 (1.27–8.22)
Axillary involvement
	No	45 (54.2)	5 (11.1)	88.9 (75.9–96.3)	0.009	1.0	0.016
	Yes	38 (45.8)	13 (34.2)	65.8 (48.6–80.4)		3.57 (1.27–10.02)
Ki-67 (%)
	≤60	34 (47.0)	5 (12.8)	87.2 (72.6–95.7)	0.066	1.0	0.077
	>60	44 (53.0)	13 (29.6)	70.4 (54.8–83.2)		2.53 (0.90–7.11)
Residual cancer burden
	pCR	42 (50.6)	1 (2.4)	97.6 (87.4–99.9)	<0.001	1.0
	RCB-I	8 (9.6)	1 (12.5)	87.5 (47.3–99.7)		4.34 (0.27–69.60)	0.300
	RCB-II	21 (25.3)	5 (23.8)	76.2 (52.8–91.8)		15.22 (1.77–130.82)	0.013
	RCB-III	12 (14.5)	11 (91.7)	8.3 (0.2–38.5)		74.10 (9.39–584.45)	<0.001
Surgical treatment
	Conservative	61 (73.5)	11 (18.0)	82.0 (70.0–90.6)	0.025	1.0	0.033
	Mastectomy	22 (26.5)	7 (31.8)	68.2 (45.1–86.1)		2.83 (1.09–7.37)

• RR: relative risk; 95%CI: 95% confidence interval; CR: pathological complete response; RCB-I: minimal burden (residual disease); RCB-II: moderate burden (residual disease); RCB-III: extensive burden (residual disease). The values highlighted in bold are intended to draw the reader's attention to statistically significant variables.

Survival curves (Figure 1) showed 10-year OS and DFS of around 61% and 65%, respectively.

Figure 1
Overall survival (A) and disease-free survival (B) curves (157 months of follow-up).

DISCUSSION

Variables such as age, number of pregnancies, alcohol dependence, hypertension, diabetes, family history of breast cancer and other cancers, degree of differentiation, and Ki-67 did not show any significant reduction in OS and/or DFS in this study. Furthermore, these variables did not present an increased risk of mortality and/or recurrence.

In this study, 60.2% of the patients were diagnosed before the age of 59 years and 79.5% had a history of previous pregnancies. In a study investigating 841 patients with TNBC diagnosed from 1994 to 2015 in four large oncology centers, Urru et al.¹³ also described that TNBC predominated in young patients with previous pregnancies.

Alcohol dependence is a well-established risk factor for the development of breast cancer. However, the literature indicates that there is no relationship between alcohol dependence and increased risk of TNBC¹⁴. Alcohol dependence is also associated with a worse chemotherapy response (first-line treatment for TNBC), worsening survival in these cases¹⁵. Alcohol-dependent patients in this study did not show a worse OS and/or DFS and an increased risk of mortality and/or recurrence.

Studies have associated hypertension, diabetes, and tumor grade with increased mortality in TNBC^16,17. However, in this study, there was also no significant reduction in OS and/or DFS and increased risk in mortality and/or recurrence, in relation to these variables.

Ki-67 and family history of breast cancer and other cancers are considered useful in the prognosis of TNBC¹⁸. Nevertheless, the literature indicates that there is controversy surrounding the methods used for analysis of these prognostic factors^9,18. In this study, Ki-67 (with a cutoff point stipulated at 60%) and a family history of breast cancer and other cancers were not implicated in a significant decrease in OS and/or DFS and increased risk of mortality and/or recurrence.

Smoking, advanced clinical stage, larger tumor size, angiolymphatic invasion, positive sentinel lymph node, axillary node involvement, higher residual tumor burden, surgical treatment with mastectomy, and recurrence were prognostic factors significantly related to a decreased OS and/or DFS, representing an increased risk of mortality and/or recurrence in TNBC, respectively. These results are based on previous literature data^19–23.

In a study of 583 patients, Mousavi et al.²⁴ demonstrated that lymph node involvement was the only prognostic factor related to decreased DFS in TNBC. However, other studies have demonstrated that a larger tumor size and residual tumor burden correlate with a higher recurrence risk and lower DFS in TNBC²⁵. Data in this study also demonstrated a higher recurrence risk and a lower DFS in relation to all these prognostic factors.

More recent analyses have indicated that breast-conserving surgery shows higher OS and DFS and lower risk of tumor recurrence, compared to mastectomy in TNBC, particularly at early stages²³. In this study, data also show a higher OS and DFS, along with a decreased risk of mortality and recurrence in patients with TNBC undergoing breast-conserving surgery.

Survival analysis in cancer is influenced by diverse variables inherent in each sample (tumor size, prevalence of tumor stage, and nature of prognostic factors, among others)²⁶. Fayaz et al.²⁷ conducted a study on the 10-year OS and DFS of 359 women diagnosed with TNBC from 1999 to 2009, indicating values of 66% for OS and 59% for DFS. These results were quite similar to findings in this study, showing that 10-year OS and DFS were 61 and 65%, respectively.

Limitations of this study were sample size, the retrospective nature of the study, and its performance in a single center.

CONCLUSION

Advanced clinical stage, positive sentinel lymph node, axillary node involvement, surgical treatment with mastectomy, and higher residual cancer burden were prognostic factors related to a statistically significant reduction in OS and DFS and an increased risk of mortality and recurrence in TNBC.

• Funding: none.

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Publication Dates

• Publication in this collection
  22 Oct 2021
• Date of issue
  July 2021

History

• Received
  02 June 2021
• Accepted
  06 June 2021