|Year : 2017 | Volume
| Issue : 4 | Page : 658-663
Triple-negative breast cancers: Are they always different from nontriple-negative breast cancers? An experience from a tertiary center in India
Suhani1, Rajinder Parshad1, Mufaddal Kazi1, V Seenu1, Sandeep Mathur2, Siddharth Dattagupta2, KP Haresh3
1 Department of Surgical Disciplines, AIIMS, New Delhi, India
2 Department of Pathology, AIIMS, New Delhi, India
3 Department of Radiation Oncology, BRAIRCH and AIIMS, New Delhi, India
|Date of Web Publication||30-Jul-2018|
Dr. Rajinder Parshad
Department of Surgical Disciplines, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
BACKGROUND: Triple-negative breast cancers (TNBCs) are known for early age at presentation, large tumor sizes, and overall poor prognosis. However, Indian studies are scarce with limited follow-up data. Hence, the present study is aimed at characterizing nonmetastatic TNBC patients in our population and comparing their outcome with non-TNBC subset. METHODOLOGY: This is a retrospective observational study of nonmetastatic breast cancer patients accrued over 14 years. The demographic, clinical, and pathological profiles of TNBCs and their patterns of recurrences and survivals were compared to that of non-TNBC. Overall and disease-free survival (DFSs) were calculated from the time of initiation of therapy to the occurrence of event, i.e., death or recurrence. RESULTS: TNBC constituted 21.8% of all patients. Patients with triple-negative subtype were significantly younger and more likely to be premenopausal. Higher proportion of TNBC presented in locally advanced stage and had a higher proportion of node-positive patients compared to their non-TNBC counterparts. Although taxane-based neoadjuvant therapy was associated with significantly higher pathological complete responses, recurrences occurred earlier in TNBC. Even though inferior overall and DFSs were encountered in TNBC, statistical significance could not be derived. CONCLUSIONS: TNBCs are a subset of tumors with a poorly understood tumor biology and behavior. Despite being labeled as having an aggressive tumor biology and behavior, not many differences are seen in their clinical outcomes when they present as locally advanced cases.
Keywords: Breast cancer, chemotherapy, taxanes, triple-negative breast cancer
|How to cite this article:|
Suhani, Parshad R, Kazi M, Seenu V, Mathur S, Dattagupta S, Haresh K P. Triple-negative breast cancers: Are they always different from nontriple-negative breast cancers? An experience from a tertiary center in India. Indian J Cancer 2017;54:658-63
|How to cite this URL:|
Suhani, Parshad R, Kazi M, Seenu V, Mathur S, Dattagupta S, Haresh K P. Triple-negative breast cancers: Are they always different from nontriple-negative breast cancers? An experience from a tertiary center in India. Indian J Cancer [serial online] 2017 [cited 2020 Jan 28];54:658-63. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/658/237890
| » Introduction|| |
Breast cancer is the second most common cancer in the world and, by far, the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012 (25% of all cancers). In India, breast cancer is the most frequently diagnosed malignancy in women accounting for 27% of all cancer cases with an age-standardized rate of 25.8/100,000 women. The panorama of breast cancer behavior and characteristics has changed from a homogeneous disease to one with unique subtypes based on gene expression profiling. Basal-like breast cancers are characterized by low-to-absent expression of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2), with a high expression of HER1 (epidermal growth factor receptor), basal cytokeratin 5/6, and c-Kit. Because staining using antikeratin antibodies is not widely available, the triple-negative phenotype (ER negative, progesterone receptor [PR] negative, and HER2 negative) is used as its surrogate as it bears 80% concordance with the basal subtype. Such patients with triple-negative disease have been reported to have a different behavior compared to nontriple-negative breast cancer (TNBC) patients in having an early age at presentation and an aggressive biology despite being more chemoresponsive. The absence of hormonal or targeted therapy against TNBC makes them a more challenging tumor subtype in terms of patient management.
However, most data on TNBC come from the Western literature where patients usually present with early breast cancers. This is in contrast to the Indian setting where patients are usually younger and tumors are locally advanced at the time of presentation., The present study is aimed at characterizing nonmetastatic TNBC patients in our population and comparing their outcome with non-TNBC subset of breast cancer patients.
| » Methodology|| |
The present study is a retrospective observational study performed in an apex tertiary care teaching and research medical institute of India. In this study, the data of breast cancer patients attending a single surgical unit run breast cancer clinic (BCC) from April 2000 to December 2014 were collected for analysis. The data were recorded from BCC files maintained since the inception of the clinic. Data regarding demography, clinical and pathological profile, treatment, responses, and outcomes were recorded. Only patients with complete information available on all the receptors (ER, PR, and HER2) were included. Patients with distant metastasis were excluded from the study. As the study included patients accrued over one and a half decades, during which there have been multiple changes in the staging system, all patients were restaged in accordance to the American Joint Committee on Cancer 7th edition. TNBCs were defined as tumors that did not stain for ER, PR, or HER2 on immunohistochemistry (IHC). HER2 was considered positive when IHC was 3 + and negative for 0 or 1+. When IHC reported 2+ (equivocal) for HER2, only those patients who underwent confirmation using fluorescent in-situ hybridization (FISH) were included in the study. Follow-up details of patients were updated during scheduled visits and with telephonic conversations. Disease-free survival (DFS) and overall survival (OS) were calculated from the time of initiation of treatment to first recurrence and death, respectively. Time-to-event variables were described using life tables and Kaplan–Meier product limit estimator. Log-rank test was used to compare Kaplan–Meier curves for survival analysis.
| » Results|| |
From April 2000 to December 2014, 1063 breast cancer patients were registered in our BCC. Of them, 179 were metastatic breast cancers and were excluded from the analysis. Of the remaining 884 patients, information regarding steroid hormone receptors and HER-2 were available for 473 patients. Among them, 25 patients had an IHC score of 2+ for HER2. Twenty-three of these 25 patients did not undergo characterization by FISH studies, and hence, were excluded from the study. Of the remaining 450 nonmetastatic breast cancer patients, 21.8% (98) of the patients were characterized as TNBCs. Following will be a comparison of those 98 TNBC patients with 352 non-TNBC patients [Figure 1].
The clinical profile of TNBCs is summarized in [Table 1].
TNBC patients presented at a younger age compared to non-TNBCs (44.4 years vs. 48 years, respectively; P = 0.006). Family history of breast cancer was noted in 1% of TNBC patients and 4% of non-TNBC patients without any statistical difference in these figures. The mean duration of lump was the same for both patient groups. Tumors of TNBC patients were larger at presentation compared to those of non-TNBC patients (6.1 cm vs. 5.2 cm, respectively; P = 0.02). Significantly higher proportions of TNBC patients were clinically node positive at presentation compared to non-TNBC patients (59.2% vs. 43.2%, respectively; P = 0.002). Proportions of locally advanced tumors in the TNBC group were 56.1% compared to 43.4% of non-TNBC; this difference was statistically significant (P = 0.005).
Upfront surgery was performed in 38.8% (38) of TNBC patients compared to 61.4% (214) in the non-TNBC group, which was significant. However, the proportion of patients undergoing mastectomy or breast conservation did not significantly differ. Pathological tumor size, nodal yield, and number of positive nodes were also not significantly different in these two groups. Tumors of TNBC patients were of higher grade with 29.6% of operated patients having Grade III tumors compared to 11.8% of non-TNBC patients (P = 0.001). There were no Grade I tumors in the TNBC group.
Neoadjuvant chemotherapy (NACT) was given to 61.2% (60) of patients in the TNBC group and 38.6% (136) of non-TNBC patients. Among chemotherapy regimens, taxanes were used in 45% of TNBC patients compared to 16.9% of non-TNBC patients in the neoadjuvant setting. Rest of the patients received anthracycline-based chemotherapy. Pathological response assessment showed significantly higher complete response (CR) rates in TNBC patients (28.8% vs. 6.7%, respectively; P = 0.025) compared to non-TNBC patients; however, overall response rates (CR + PR) in TNBC patients were similar to that of non-TNBC patients (84.7% vs. 73.1%, respectively; P = 0.06). The CR rates were higher in TNBC patients receiving NACT. In addition, higher CR rates were seen with taxane-based chemotherapy [Table 2].
Mean follow-up durations were 4.1 years in TNBC patients and 4.7 years in non-TNBC patients.
The 5-year OS for TNBC patients was 72.9% compared to 72.8% in non-TNBC patients, giving a hazard ratio of 1.154 (P = 0.59). The 5-year DFS was 55.6% for TNBC patients and 65.7% for non-TNBC patients (hazard ratio - 1.332; P = 0.19). These differences, however, were not significant [Figure 2]a and [Figure 2]b.
|Figure 2: (a) Survival trends in triple-negative breast cancer and nontriple-negative breast cancer patients as depicted by overall survival. (b) Survival trends in triple-negative breast cancer and nontriple-negative breast cancer patients as depicted by disease-free survival|
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Overall, 118 recurrences were noted in the 450 patients included in the study. Approximately 28.6% of TNBC (28) patients recurred and 27.4% of non-TNBC (90) patients had recurrences (P = 0.54) over a follow-up duration ranging from 1 year to 15 years. Of the TNBC patients, 66.3% were alive at the end of the study period without disease, 9.2% were alive with recurrences, 18.4% had expired, and 6.1% were lost before completion of 2 years of follow-up period. In the non-TNBC group, 69.3% were alive without disease, 5.7% were alive with recurrences, 19.9% had expired, and 5.1% were lost to follow-up.
Maximum recurrences were observed between the 1st and 2nd years of follow-up in the TNBC group (42.8% of all recurrences) whereas the non-TNBC patients recurred maximally between the 2nd and 5th years (45.5% of all recurrences). There were 18 distant recurrences in TNBC patients, 28% (5) of them involved the central nervous system (CNS), whereas only 6% (4) of all distant recurrences in non-TNBC patients had CNS involvement (P = 0.005). There were no isolated bone metastases in the TNBC group compared to 24% (16 patients) of all distant recurrences restricted to the skeletal system in non-TNBC patients (P = 0.02). The trends of recurrences and metastasis sites are shown in [Figure 3] and [Figure 4], respectively.
|Figure 3: Trends in recurrences (percentage of total recurrences over follow-up)|
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|Figure 4: Sites of distant metastasis in follow-up (soft-tissue metastasis represents distant nodal or subcutaneous metastasis)|
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| » Discussion|| |
TNBCs are a subset of breast cancer patients that pose a therapeutic challenge to the clinician because of their aggressive nature and a lack of targeted therapy against them. Higher occurrence rates of TNBC have been found in certain ethnicities such as Hispanic and African, as well as among individuals with lower socioeconomic status, BRCA1 mutation, and younger patients.
In our study, TNBC patients constituted approximately 21.8% of the study population. As per the Western literature, TNBC accounts for approximately 10%–20% of all breast cancers, with a prevalence of 12.5% reported in a large, California population-based study reported by Bauer et al. The National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database of newly diagnosed nonmetastatic unilateral breast cancer from January 2000 to December 2006 revealed that 17% of their patients were triple negative. However, most Indian studies report a higher rate of TNBC; Agarwal et al. reported that TNBC patients constituted around 35.3% of their cohort of breast cancer patients. Similarly, Ghosh et al. found almost 30% of their cancers to be TNBC. Though our percentage of TNBC patients is in concordance with the Western data, the relatively low number of TNBC patients in our study compared to other Indian studies might be due to the fact that all cases with equivocal results (Her2neu 2 + on IHC) in whom confirmation of receptor status by FISH was not available were excluded from the study. FISH was done in only one patient with equivocal (2+) results. Furthermore, only nonmetastatic patients were included in our study.
TNBC patients presented at a younger age as compared to non-TNBCs (44.4 years vs. 48 years, respectively; P = 0.006). Similar findings were also been observed in other studies. Nearly 53.6% of the TNBC patients were premenopausal which was not significantly different from the non-TNBC group.,
Our study found that TNBC presented with larger tumors with a mean lump size of 6.1 cm (non-TNBC = 5.2 cm, P = 0.02). Dent et al. reported 8% of tumors >5 cm in the TNBC group compared to 4.6% of the non-TNBC group. This number, though small, in the study by Dent et al. is significant as most tumors are detected by screening mammography in the West. Fifty-six percent of our patients presented with locally advanced cancers whereas only 43.4% presented with locally advanced cancers in the non-TNBC group (P = 0.005). Nabi et al. reported 45% of Stage III tumors in the TNBC group compared to 35.5% in the non-TNBC group. This represents likely different tumor biology of these rapidly growing tumors. The reason behind the larger tumor size and advanced stage at presentation of TNBC remains largely unknown. Whether these tumors are receptor negative to start with or whether they start as usual breast cancers and then outgrow the cellular control mechanisms and lose expression of these receptors to acquire an aggressive growth pattern remains unknown. The higher proportion of locally advanced tumors in the TNBC group is a consistent finding in the literature, and unlocking of these aspects in tumor biology may help in better understanding of these tumors.
A higher proportion of patients with nodal metastasis were seen in the TNBC group with almost 60% of patients having clinically positive axillary node status. The relationship between node positivity and TNBC has been conflicting in the existing literature. Agarwal et al. reported a higher incidence of clinically involved nodes in TNBC patients compared to non-TNBC patients (77.3% vs. 69.8%, respectively, P = 0.03). Dent et al. studied 180 patients with TNBC and compared their profile with that of non-TNBC patients. They found that nodal metastasis was significantly higher in TNBC patients than that in non-TNBC patients (54.6% vs. 45.6%, respectively, P = 0.02). They also highlighted that, while in the non-TNBC subgroup of patients, there was an increased incidence of nodal involvement as the tumor size increased; this relationship was not seen in the TNBC subgroup which had increased likelihood of node positivity even in smaller tumor size. The authors reported that only 10% of tumors <1 cm had nodal metastasis whereas >90% of tumors >5 cm had nodal metastasis in the non-TNBC group. However, this correlation was not seen in the TNBC group with 55% of tumors ≤1 cm having nodal metastasis. In our study, there was no statistically significant difference in pathological lymph node positivity in axillary lymph-node dissection specimens in both patient groups undergoing upfront surgery. This is likely because the average size of tumor in either group was not significantly different (3.45 for non-TNBC vs. 3.65 cm for TNBC), and these represented early-stage diseases with low tumor burden undergoing upfront surgery. However, an observation contrary to the study by Dent et al. was made by Lin et al. who found that triple-negative tumors are less likely to be node positive than either HER2+ or HER2+/HER2−tumors, especially when the tumor size is >2 cm. These conflicting results further emphasize that the missing links in the tumor biology of TNBCs need to be unraveled for a better understanding of these tumors.
Aggressiveness of triple-negative tumors also stems from their higher grade. Almost 30% (29.6%) of TNBC patients had Grade III tumors compared to 11.8% of non-TNBC patients. There were no Grade I tumors in the TNBC group. Agarwal et al. reported 56.4% Grade III tumors in their study. In one of the largest studies on TNBC from a single institution, the proportion of Grade III tumors was 66% in TNBC patients and 28% in non-TNBC patients. Lakshmaiah et al. reported 88% of TNBC patients to have high-grade tumors. The smaller number of higher grade tumors in our study might stem from the fact that only Grade III tumors were included as high grade, whereas other studies included both Grade II and III tumors in the high-grade category. Furthermore, we excluded patients with HER-2 score of 2+ on IHC from the analysis when FISH was unavailable as well as those with metastatic disease. FISH is performed at our institution only for patients who can afford trastuzumab therapy.
Triple-negative subtypes have high S-phase fraction and are more sensitive to chemotherapy. We found that, although the overall response to NACT was similar in TNBC and non-TNBC groups (84.7% of TNBC patients vs. 73.1% of non-TNBC patients), higher CR rates were observed for TNBC patients receiving NACT compared to non-TNBC patients (28.8% vs. 6.7%, respectively). Studies have also shown that the type of chemotherapeutic regimen used in NACT affects the response rates within the TNBC group, with taxane-based regimens having a statistically better response to nontaxane-based regimens. In our study, the pathological complete response (pCR) rates were significantly higher in the taxane-based group compared to anthracycline-/nontaxane-based group. This might also explain, at least partially, the higher response rates in TNBC group patients as they more often received taxane-based chemotherapy. Lakshmaiah et al. reported that all 24 patients who received NACT in their study (23 anthracycline based and 1 taxane based) had a partial response. Their relatively poor response rates in terms of absence of pCR can be explained on the basis of chemotherapeutic agent used. Suresh et al. found 75% of overall response rates for NACT, of which 25% of the patients with locally advanced breast cancer (LABC) had CR. In addition, all these pCR patients received taxane-based NACT. Our results are further supported by a meta-analysis on the association between pCR and tumor subtypes by Wu et al. who found that 29% of TNBC patients achieved pCR compared to 12.5% of non-TNBC patients.
TNBC disease did not contraindicate breast conservation in our patients, with equal proportion of patients undergoing mastectomy and conservations in either patient group. Kim et al. reported in their study that breast conservation remains a feasible option in patients with TNBC with similar DFS and OS compared to mastectomy in suitably selected patients. Similar results were also reported by Agarwal et al. from India who showed that approximately 20% of patients underwent breast conservation surgery in both TNBC and non-TNBC groups.
Irrespective of the disease subtype, >80% of all recurrences occurred within 5 years of follow-up in our study. Peak recurrences were noted significantly earlier in TNBC patients with a sharp fall in the rate of recurrences after 2 years of follow-up. Our results are similar to those reported by Lin et al. in their NCCN database where the difference in the risk of recurrences and death was maximum till the 2nd year of follow-up. Recurrence patterns were significantly different between TNBC and non-TNBC groups. In our study, CNS metastasis was seen in 28% of patients and isolated skeletal metastasis (commonly seen in non-TNBC patients) was not seen in any patient. Lin et al. reported that women with triple-negative tumors were more likely to experience the first recurrence in brain, lung, or locoregional sites, and are less likely to recur in bone. In addition, the CNS was initially involved in 13% (62/480) and ever involved in 36% of TNBC patients. Dent et al. reported majority of the recurrences to be in the lung and CNS, and very few were preceded by locoregional recurrence. Suresh et al., in 171 TNBC patients with a median follow-up of 30 months, reported 34 recurrences. There were 25 systemic recurrences with lung and CNS relapses (13) being almost four times compared to bone (three).
Even though inferior DFS was observed for TNBC patients in our study, the differences did not attain statistical significance. This may be because only nonmetastatic patients were included in the present study. In addition, even in the non-TNBC group, a significant proportion of patients were seen in the LABC category, reemphasizing the fact that tumor burden plays an important role in disease prognosis. In the study by Agarwal et al., the OS and DFS of TNBC patients were found to be poorer than those of non-TNBC patients. However, on subgroup analysis, the survival difference was not seen in Stage I and II patients. Our results are further supported by those reported by Eralp et al.; tumor size and presence of lymph node metastasis were independent factors that have an effect on DFS, and higher tumor stage was the only negative prognostic factor for OS. Lin et al. found a significantly poor breast cancer-specific survival and OS in TNBC patients compared to non-TNBC patients, irrespective of factors such as age, stage, nodal status, tumor grade, or use of adjuvant chemotherapy. Similarly, Dent et al. found that patients with TNBC had a higher mortality than non-TNBC patients (42.2% vs. 28%, respectively; P < 0.0001) with a significantly early median time to death (4.2 years for TNBC patients vs. 6 years for non-TNBC, P < 0.0001). However, in most studies from Western countries, Stage I and II tumors represent a majority of the cases.
To summarize, our study suggests that TNBC occurs more commonly in younger, premenopausal women. They have a larger tumor size at presentation as well as better response to neoadjuvant chemotherapeutic agents. Despite a good response to NACT, their recurrences are more often earlier and more commonly seen at critical sites such as CNS. However, we did not find any difference in OS or DFS between the TNBC and non-TNBC groups.
| » Conclusions|| |
TNBCs are a subset of tumors with an enigmatic and poorly understood tumor biology and behavior. Despite being labeled as having an aggressive tumor biology and behavior, not many differences are seen in their clinical outcomes when they present as locally advanced cases. If this holds true, then understanding the tumor biology of early-stage TNBCs in this subset remains an area of future research and study.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]