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Disease Behavior and Treatment Response of Special Histological Types of Triple-Negative Breast Cancer

Published:August 19, 2022DOI:https://doi.org/10.1016/j.clbc.2022.08.006

      Abstract

      Background

      : Special histological types (SHT) of triple-negative breast cancer (TNBC) are a heterogeneous group of rare poorly understood diseases. We aimed to evaluate the clinical features, treatment, and outcomes of patients with SHT of TNBC.

      Methods

      : We evaluated patients with a SHT of TNBC treated in a cancer center between 2009 and 2020. The endpoints were characterization of clinical and pathological features, pathologic complete response (PCR) rate after neoadjuvant chemotherapy, disease-free survival (DFS), progression-free survival, and overall survival (OS).

      Results

      : The 132 patients included had the following histologies: metaplastic (n=71), medullary pattern (n=14), lobular (n=12), adenoid cystic (n=12), apocrine (n=10), and others (n=13). Metaplastic, lobular, and medullary pattern tumors had higher grade (66.6–85.7% grade 3); adenoid cystic and apocrine had mainly grade 1-2 (70–83.3%). Metaplastic and lobular carcinomas had higher disease stages (47.8% and 58.2% stages III-IV). PCR rates were 10.3% for metaplastic and 33.3% for lobular carcinomas, with 5-year DFS rates of 56% and 51.4%. Medullary pattern carcinomas had a great response to treatment, with PCR rate of 100%, and 5-year DFS rate of 92.8%. Apocrine carcinomas also had favorable prognosis, with no recurrence after early disease treatment, and 5-year DFS rate of 83.3%. Adenoid cystic carcinomas had intermediate prognosis, with 5-year DFS rate of 66.6%.

      Conclusion

      : SHT of TNBC encompasses heterogeneous malignancies with distinct behaviors. Lobular and metaplastic carcinomas showed high aggressiveness and poor treatment response, while medullary pattern and apocrine carcinomas had favorable outcomes. Treatment strategies focus on molecular features of each of these diseases are warranted.

      Keywords

      Introduction

      Triple-negative breast cancer (TNBC) comprises 10 to 15% of breast cancer cases and its treatment still represents a key challenge
      • Bauer KR
      • Brown M
      • Cress RD
      • Parise CA
      • Caggiano V.
      Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
      ,
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      • Karaca G
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      • et al.
      Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.
      . Although TNBC is usually approached as a single disease, this group encompasses extremely heterogeneous diseases that differ in several aspects, such as epidemiology, histology, and gene expression, and consequently presents different clinical behavior, response to treatment, and survival
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      Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
      ,
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      • López-Tarruella S
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      • Jerez Y
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      • et al.
      Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification.
      . Breast carcinoma of no-special type (or ductal breast carcinoma) is the most common histology, but about 25% of the breast carcinomas are special histological types
      • Lakhani S
      • Ellis I
      • Schnitt S
      • Tan P
      • van de Vijver M.
      WHO classification of tumours of the breast.
      .
      To illustrate the diversity of TNBC special histological types, this group includes aggressive diseases with high proliferation index such as metaplastic and lobular carcinomas, as well as more indolent diseases with low proliferation index such as apocrine carcinomas
      • Mills AM
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      Pure Apocrine Carcinomas Represent a Clinicopathologically Distinct Androgen Receptor-Positive Subset of Triple-Negative Breast Cancers.
      . While metaplastic carcinomas are frequently chemoresistant and have a poor prognosis, medullary pattern carcinomas usually have a great response to treatment
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      Rare Breast Cancer Subtypes.
      . Nevertheless, since each of the TNBC special histologies is extremely rare and still poorly understood, they are often treated in the same way as the TNBC of no special type, without taking into account the differences between them.
      In this study, we retrospectively selected special histologies of TNBC, including metaplastic, lobular, medullary, adenoid cystic, papillary, and apocrine carcinomas. Our objective was to assess the epidemiology, clinical behavior, and response to treatment of the TNBC special histological types.

      Methods

      Study design and participants

      This retrospective cohort included patients with special histological types of triple-negative breast cancer treated from 2009 to 2020 at the Instituto do Câncer do Estado de São Paulo (ICESP, São Paulo, Brazil). ICESP is a tertiary cancer center that assists over 10,000 new cancer cases per year. Patients included had histologically confirmed triple-negative breast cancer with one of the following histological types: metaplastic, lobular, medullary, adenoid cystic, or apocrine. Breast cancer was considered triple-negative if estrogen receptor and progesterone receptor expression was lower than 1% and HER2 (Human Epidermal Growth Factor Receptor 2) was not amplified (HER2 score lower than 3+ in immunohistochemistry or negative in situ hybridization). Patients with any disease stage were included. Non-epithelial breast malignancies, such as sarcomas, phyllodes tumors, or lymphomas were not included.
      The study endpoints were the description of clinical and pathological characteristics, pathologic complete response rate of patients treated with neoadjuvant chemotherapy, disease-free survival (DFS) for early breast cancer, progression-free survival (PFS) for advanced breast cancer, and overall survival (OS). Response to neoadjuvant chemotherapy was based on physical exam, breast image (mammogram, ultrasound and/or magnetic resonance imaging) and pathology results. Pathologic complete response was defined as the absence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant chemotherapy. Electronic records were reviewed for data collection. Clinical and demographic data evaluated comprised age, race, body mass index, personal and family history of cancer, disease stage, tumor grade, and Ki67 index. The treatment received and oncologic outcomes were revised and detailed.
      The data were collected using electronic case report forms (RedCap®). The study was approved by the Local Ethics Committee.

      Statistical analysis

      Patients’ characteristics and treatments received were tabulated and compared. Continuous variables were presented using median and range and compared between groups using one-way ANOVA. Categorical data were presented using absolute and relative frequencies and compared using Fisher exact test.
      Survival analyses were estimated by the Kaplan-Meier method, with the use of the log-rank test to compare the survival curves. The Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI). DFS was estimated from the date of diagnosis until the date of disease recurrence (local or distant recurrence) or death. PFS was estimated from the date of initiation of first-line chemotherapy until disease progression or death. OS was the time from the date of breast cancer diagnosis or the date of diagnosis of advanced disease for patients with advanced disease (at diagnosis or after recurrence) to the date of death from any cause. Patients without the events were censored at the date of the last follow-up.
      The Stata software version 15.1 (StataCorp, Texas, USA) was used for the statistical analysis. P-values lower than 0.05 were considered statistically significant.

      Results

      Patients’ characteristics

      A total of 132 women with special histological types of triple-negative breast cancer were evaluated. The most common histology was metaplastic, with 71 cases. Others were medullary (n=14), lobular (n=12), adenoid cystic (n=12), apocrine (n=10). Thirteen patients had other histological types (clear cell, papillary, secretory, and squamous cell carcinoma) and were not evaluated separately due to the small number of patients in each group. Median follow-up was 42.4 months.
      Clinical and pathological features differed importantly according to the special histological type (Table 1). Patients with metaplastic, medullary, and adenoid cystic carcinomas had younger median ages (51 to 53 years), while those with apocrine carcinomas were older (median age of 66 years) (P=0.009). More advanced disease stages were observed in metaplastic, apocrine, and lobular carcinomas, with 47 to 58% of stage III-IV disease. Otherwise, medullary and adenoid cystic carcinomas presented with earlier disease stages (57% and 75% were stage I-II). Lobular, metaplastic, and medullary carcinomas had higher tumor grades (66 to 85% of grade 3 tumors) and Ki67 index (median of 55 to 70%). Apocrine and adenoid cystic carcinomas had lower grades (70 and 83% of grade 1-2 tumors) and Ki67 index (median of 20% and 22.5%) (P<0.001 for both grade and Ki67 index).
      Table 1Clinical and pathological characteristics of the patients with special histological types of triple-negative breast cancer. Abbreviations: AC, adenoid cystic; IHC, immunohistochemistry; ISH, in situ hybridization.
      Metaplastic

      (n=71)
      Medullary

      (n=14)
      Lobular

      (n=12)
      AC

      (n=12)
      Apocrine

      (n=10)
      P-Value
      Age (median, range)51

      (22 – 83)
      53

      (34 – 74)
      56

      (28 – 84)
      53

      (40 – 78)
      66

      (46 – 90)
      0.009
      Stage at diagnosis (n, %)

      I-II

      III

      IV


      34 (47.8%)

      30 (42.2%)

      4 (5.6%)


      8 (57.1%)

      5 (35.7%)

      1 (7.1%)


      5 (41.6%)

      5 (41.6%)

      2 (16.6%)


      9 (75%)

      1 (8.3%)

      1 (8.3%)


      5 (50%)

      4 (40%)

      1 (10%)
      0.205
      Grade (n, %)

      1

      2

      3


      0 (0%)

      16 (22.5%)

      53 (74.6%)


      0 (0%)

      1 (7.1%)

      12 (85.7%)


      1 (8.3%)

      3 (25%)

      8 (66.6%)


      4 (33.3%)

      6 (50%)

      2 (16.6%)


      1 (10%)

      6 (60%)

      3 (30%)
      <0.001
      Ki67, % (median, range)70

      (20 – 100)
      55

      (5 – 95)
      65

      (6 – 90)
      22.5

      (10 – 70)
      20

      (5 – 70)
      <0.001
      HER2 score

      IHQ 0+

      IHQ 1+

      IHQ 2+ with negative ISH

      Negative, not detailed


      43 (60.6%)

      5 (7%)

      1 (1.4%)

      22 (31%)


      3 (21.4%)

      0 (0%)

      0 (0%)

      11 (78.6%)


      8 (66.7%)

      0 (0%)

      1 (8.3%)

      3 (25%)


      8 (66.7%)

      0 (0%)

      0 (0%)

      4 (33.3%)


      4 (40%)

      2 (20%)

      2 (20%)

      2 (20%)
      0.101
      Fisher's exact test, evaluating only the patients who had the HER2 score detailed.
      Metaplastic subtype

      Adenosquamous

      Squamous cell

      Spindle cell

      Mesenchymal differentiation

      Matrix producing

      Mixed

      Other

      Not available


      3 (4.2%)

      18 (25.3%)

      4 (5.6%)

      16 (22.5%)

      18 (25.3%)

      7 (9.8%)

      2 (2.8%)

      3 (4.2%)
      ----
      AC subtype

      Classic

      Solid/ Basaloid

      Other

      Not available
      ---

      2 (16.7%)

      3 (25%)

      2 (16.7%)

      5 (41.7%)
      low asterisk Fisher's exact test, evaluating only the patients who had the HER2 score detailed.
      Eight-five patients had the HER2 score detailed, and 85.9% of them were HER2 zero in immunohistochemistry. The HER2 zero score was the most common among the different subtypes, with the exception of apocrine carcinomas (Table 2). Among the apocrine carcinomas, 8 patients had HER2 score detailed; half of them (n=4) would be considered HER2-low, with two HER2 1+ and two HER2 2+ with negative in situ hybridization.
      Table 2Treatment received and outcomes of patients with special histological types of triple-negative breast cancer. Abbreviations: AC, adenoid cystic; NCT, neoadjuvant chemotherapy; CT, chemotherapy; DFS, disease-free survival; PFS, progression-free survival; OS, overall survival; mo, months; NA, not applicable.
      MetaplasticMedullaryLobularACApocrineP-Value
      Early disease(n=64)(n=14)(n=10)(n=11)(n=9)
      NCT, n (%)29 (45.3%)7 (50%)6 (60%)3 (27.3%)2 (22.2%)-
      Response to NCT, n (%)

      Complete response

      Partial response

      Stable disease

      Progressive disease

      NA


      3 (10.3%)

      15 (51.7%)

      4 (13.8%)

      6 (20.7%)

      1 (3.4%)


      7 (100%)

      0 (0%)

      0 (0%)

      0 (0%)

      0 (0%)


      2 (33.3%)

      1 (16.7%)

      0 (0%)

      1 (16,7%)

      2 (33.3%)


      0 (0%)

      2 (66.6%)

      1 (33.3%)

      0 (0%)

      0 (0%)


      0 (0%)

      0 (0%)

      2 (100%)

      0 (0%)

      0 (0%)
      <0.001
      Type of surgery, n (%)

      Mastectomy

      Conservative

      No surgery

      NA


      44 (68.7%)

      17 (26.6%)

      1 (1.6%)

      2 (3.12%)


      3 (21.4%)

      10 (71.4%)

      1 (7.1%)

      0 (0%)


      6 (60%)

      2 (20%)

      0 (0%)

      2 (20%)


      3 (27.3%)

      8 (72.7%)

      0 (0%)

      0 (0%)


      4 (44.4%)

      5 (55.6%)

      0 (0%)

      0 (0%)
      0.002
      Radiation therapy

      Yes

      No

      NA/ Not applicable


      46 (71.9%)

      15 (23.4%)

      3 (4.7%)


      11 (78.6%)

      3 (21.4%)

      0 (0%)


      7 (70%)

      2 (20%)

      1 (10%)


      9 (81.8%)

      2 (18.2%)

      0 (0%)


      7 (77.8%)

      2 (22.2%)

      0 (0%)
      0.962
      Disease recurrence, n (%)21 (32.8%)

      1 (7.1%)3 (30%)3 (27.3%)0 (0%)0.100
      Sites of recurrence

      Local only

      Distant only

      Both


      0 (0%)

      14 (21.9%)

      7 (10.9%)


      0 (0%)

      1 (7.1%)

      0 (0%)


      1 (10%)

      2 (20%)

      0 (0%)


      0 (0%)

      2 (18.2%)

      1 (9.1%)


      0 (0%)

      0 (0%)

      0 (0%)
      0.358
      Sites of distant recurrence

      1

      2

      3

      4

      5

      6

      7


      1 (1.6%)

      15 (51.7%)

      2 (3.12%)

      4 (13.8%)

      6 (20.7%)

      4 (13.8%)

      0 (0%)


      1 (7.1%)

      0 (0%)

      0 (0%)

      1 (7.1%)

      0 (0%)

      0 (0%)

      0 (0%)


      1 (10%)

      1 (10%)

      0 (0%)

      1 (10%)

      2 (20%)

      0 (0%)

      0 (0%)


      2 (18.2%)

      2 (18.2%)

      0 (0%)

      1 (9.1%)

      1 (9.1%)

      0 (0%)

      1 (9.1%)


      0 (0%)

      0 (0%)

      0 (0%)

      0 (0%)

      0 (0%)

      0 (0%)

      0 (0%)
      -
      5y-DFS rates, % (95% CI)56.0

      (41.0 – 68.6)
      92.8

      (59.0 – 98.9)
      51.4

      (16 – 78.5)
      66.6

      (28.1 – 87.8)
      83.3

      (27.3 – 97.4)
      0.074
      5y-OS rates, % (95% CI)63.3

      (47.9 – 75.3)
      92.3

      (56.6 – 98.8)
      64.2

      (24.4 – 87)
      88.8

      (43.3 – 98.3)
      83.3

      (27.3 – 97.4)
      0.142
      Advanced disease(n=28)(n=1)(n=4)(n=4)(n=1)
      1st line CT (n, %)

      Platinum-based

      Taxane

      Anthracycline-based

      Other


      14 (58.3%)

      6 (25%)

      6 (25%)

      2 (8.3%)


      1 (100%)

      0 (0%)

      0 (0%)

      0 (0%)


      0 (0%)

      2 (100%)

      0 (0%)

      0 (0%)


      1 (100%)

      0 (0%)

      0 (0%)

      0 (0%)


      NA
      0.206
      Median PFS, months4.3 moNANANANA-
      Median OS, months13.3 moNANANANA-

      Outcomes – early breast cancer

      Among 118 patients who presented with early breast cancer at diagnosis, 51 received neoadjuvant chemotherapy and 44 received adjuvant chemotherapy. Ninety-two percent of the patients treated with neoadjuvant chemotherapy and 68% of those treated with adjuvant chemotherapy received a regimen based on anthracyclines and taxanes.
      Diverse disease behaviors and responses to therapy were observed depending on the special histological type. All patients with medullary carcinomas who received neoadjuvant chemotherapy achieved a pathologic complete response (n=7/7, 100%) compared to none of those with adenoid cystic (n=0/3, 0%) or apocrine (n=0/2, 0%) tumors. Pathologic complete response rates were 10.3% (n=3/29) for metaplastic and 33.3% (n=2/6) for lobular carcinomas. The presence of pathologic complete response was a favorable prognostic factor, with a 5-year DFS of 100% among patients with pathologic complete response compared to 48.6% among those with residual disease after neoadjuvant chemotherapy (P=0.003). Figure 1 shows the Kaplan-Meier curves for DFS of patients treated with neoadjuvant chemotherapy according to the pathologic response.
      Figure 1
      Figure 1Disease-free survival of patients with special histologic subtypes of triple-negative breast cancer treated with neoadjuvant chemotherapy according to the pathologic response. Abbreviations: PCR, pathologic complete response.
      The 5-year DFS rates were numerically lower among patients with metaplastic and lobular carcinomas (56% and 51.4%). The 5-year DFS rates were 66.6%, 92.8%, and 83.3% for those with adenoid cystic, medullary, and apocrine tumors (P log-rank =0.074), respectivelly. The OS for early disease followed this same pattern, with numerically lower 5-year OS rates for metaplastic (63.3%) and lobular (64.2%) carcinomas.
      Figure 2 illustrates the Kaplan-Meier curves for DFS and OS according to the special histological type. The oncologic outcomes of the special histological types of triple-negative breast cancer are summarized in Table 2.
      Figure 2
      Figure 2Disease-free survival (A) and overall survival (B) of patients with triple-negative early breast cancer according to the special histologic subtype.

      Outcomes – advanced breast cancer

      Forty-three patients had metastatic disease at diagnosis (n=16) or after disease recurrence (n=32). The most common first-line chemotherapy regimens were platinum-doublets (n=16, 37%), taxanes (n=10, 23%), and anthracyclines (n=7, 16%) (Table 2).
      Due to the small sample sizes of the other groups, the oncologic outcomes for advanced breast cancer were evaluated only for metaplastic carcinomas. Median PFS of patients with metaplastic carcinoma after initiation of first-line chemotherapy was 4.3 months (Figure 3A). Median PFS was 5.4 months for patients who received first-line platinum regimens compared to 4.3 months for those treated with other regimens (HR 0.76, 95% CI 0.31 – 1.86, P=0.556). Median OS after the diagnosis of advanced disease was 13.3 months (Figure 3B).
      Figure 3
      Figure 3Progression-free survival (3A) after first-line chemotherapy initiation and overall survival (3B) after diagnosis of advanced disease of patients with metaplastic breast carcinoma.

      Discussion

      The present study highlights the high heterogeneity of the special histological types of TNBC and provides further data on each type's behavior. In our cohort, most patients had localized disease at diagnosis (89%). Metaplastic carcinomas were the most frequent special histology. These tumors are characterized by the differentiation of the neoplastic epithelium into squamous cells and/or elements with mesenchymal characteristics, including spindle cells, chondroids, bone, rhabdomyoids, among others
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      . They are usually triple-negative and express keratins 5/6 and 14 and EGFR. Its incidence ranges from 0.2 to 1% of all invasive breast cancers. Compared with non-special type carcinoma, metaplastic carcinomas present as larger tumors at diagnosis, with less lymph node involvement and higher histological grade, as observed in the present study
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      Despite being an aggressive and fast-growing disease, most cases of metaplastic TNBC had localized disease at the time of diagnosis (89%) in our cohort. Twenty-nine patients received neoadjuvant chemotherapy, of which 62% (n = 18) had a response; but only 3 achieved a pathologic complete response (10.3%). Six patients (20.7%) experienced disease progression during neoadjuvant chemotherapy. These results are in accordance with previous literature showing a pathologic complete response of 10 - 17% among patients with metaplastic carcinomas treated with neoadjuvant chemotherapy
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      . In addition, recurrence rates were high, with a 5-year DFS of 56%. Based on the literature results, many physicians prefer not to offer neoadjuvant treatment for this group of patients. However, we believe that for a very aggressive disease as metaplastic breast cancer, an overall response rate above 60% justifies prospective studies for clarifying the benefits of this approach and, until we have these results, patients should not be generally deprived of neoadjuvant treatment.
      Facing the low sensitivity to standard antineoplastic treatments and the poor prognosis of metaplastic carcinomas, the development of better personalized therapies is urgently needed. The broadening of next-generation sequencing is contributing to the comprehension of molecular features of special histologies. Regarding metaplastic carcinomas, a high frequency of p53 and PIK3CA mutations has been described
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      . Thus, drugs targeting the PI3K/AKT/mTOR pathway represent an interesting potential therapy to be investigated. Results from phase 1 trials investigating the mTOR inhibitors everolimus and temsirolimus for advanced metaplastic breast carcinomas have been reported. The addition of the mTOR inhibitor to bevacizumab and liposomal doxorubicin achieved response rates of 21 to 42%
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      , and a phase II trial is currently ongoing (NCT02456857).
      Immune checkpoint inhibitors are another promising treatment possibility. Phase 3 trials demonstrated the efficacy of the PD-1 inhibitor pembrolizumab for early and advanced TNBC of no-special type, while its activity for special types still requires further investigation. Biomarkers that potentially predict response to immunotherapy have been frequently observed in metaplastic carcinomas. Around 50 to 70% of metaplastic carcinomas present PD-L1 expression, a proportion higher than that observed in TNBC of no-special type
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      Lobular TNBC also presented a poor prognosis, similar to metaplastic carcinomas, with a 5-year DFS of 51.4% for patients with early disease. Invasive lobular carcinoma is the most common of the special types, accounting for up to 15% of all breast cancer cases
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      . However, classic lobular carcinomas are characterized by a lack of E-cadherin and a predominantly luminal A molecular pattern.  In contrast, the triple-negative variant is a rare and aggressive disease
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      • Yang GQ
      • Oliver DE
      • Liveringhouse CL
      • Ahmed KA
      • Orman AG
      • et al.
      Histologic heterogeneity of triple negative breast cancer: A National Cancer Centre Database analysis.
      . According to Lehmann's refining classification, lobular TNBC usually have a luminal androgen receptor (LAR) subtype, characterized by luminal gene expression and driven by the androgen receptor (AR)
      • Lehmann BD
      • Jovanović B
      • Chen X
      • Estrada MV
      • Johnson KN
      • Shyr Y
      • et al.
      Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
      . Echavarria et al showed that LAR tumors have the lowest pathologic complete response rates after neoadjuvant chemotherapy
      • Echavarria I
      • López-Tarruella S
      • Picornell A
      • García-Saenz J
      • Jerez Y
      • Hoadley K
      • et al.
      Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification.
      . The lobular TNBC chemoresistance and the possible driven role of the AR pathway lead to the rationale for investigating anti-androgen therapies for this disease
      • Echavarria I
      • López-Tarruella S
      • Picornell A
      • García-Saenz J
      • Jerez Y
      • Hoadley K
      • et al.
      Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification.
      . Nevertheless, studies evaluating these agents for TNBC so far did not specify the histological type
      • Gucalp A
      • Tolaney S
      • Isakoff SJ
      • Ingle JN
      • Liu MC
      • Carey LA
      • et al.
      Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer.
      • Traina TA
      • Miller K
      • Yardley DA
      • Eakle J
      • Schwartzberg LS
      • O'Shaughnessy J
      • et al.
      Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer.
      • Bonnefoi H
      • Grellety T
      • Tredan O
      • Saghatchian M
      • Dalenc F
      • Mailliez A
      • et al.
      A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).
      .
      Apocrine TNBC are also known for the frequent expression of AR receptor
      • Farmer P
      • Bonnefoi H
      • Becette V
      • Tubiana-Hulin M
      • Fumoleau P
      • Larsimont D
      • et al.
      Identification of molecular apocrine breast tumours by microarray analysis.
      , but unlike lobular, they seem to have a better prognosis. Nevertheless, considering the rarity of the disease, its prognosis is still a matter of debate. Much rarer than its peers, apocrine TNBC represents around 0.4 - 4%, and data about surveillance are imprecise
      • Wu W
      • Wu M
      • Peng G
      • Shi D
      • Zhang J.
      Prognosis in triple-negative apocrine carcinomas of the breast: A population-based study.
      . Apocrine differentiation leading to metaplasia and carcinoma is an accepted theory for the development of these tumors
      • Arciero CA
      • Diehl AH
      • Liu Y
      • Sun Q
      • Gillespie T
      • Li X
      • et al.
      Triple-negative apocrine carcinoma: A rare pathologic subtype with a better prognosis than other triple-negative breast cancers.
      . As well as metaplastic carcinomas, apocrine TNBC presents increased rates of PIK3CA, TP53, and MYC mutations
      • Jenkins S
      • Kachur ME
      • Rechache K
      • Wells JM
      • Lipkowitz S.
      Rare Breast Cancer Subtypes.
      . Unlike metaplastic or lobular TNBC, however, our results points to a good prognosis of apocrine carcinomas
      • Arciero CA
      • Diehl AH
      • Liu Y
      • Sun Q
      • Gillespie T
      • Li X
      • et al.
      Triple-negative apocrine carcinoma: A rare pathologic subtype with a better prognosis than other triple-negative breast cancers.
      . No disease recurrence was observed among patients treated for early disease. The only DFS event that occurred was a death not related to apocrine carcinoma. Nevertheless, the response to chemotherapy was also poor. Only two cases were treated with neoadjuvant chemotherapy, both presenting stable disease. Sun et al published a cohort of 18 cases with genomic analysis, and describe 17 of them having at least one actionable alteration, raising the interest in the potential of targeted therapies
      • Sun X
      • Zuo K
      • Yao Q
      • Zhou S
      • Shui R
      • Xu X
      • et al.
      Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas.
      . Androgen deprivation led to disease control for one year in a rare case report of metastatic apocrine breast cancer
      • Jongen L
      • Paridaens R
      • Floris G
      • Wildiers H
      • Neven P.
      Androgen deprivation by adrenal suppression using low-dose hydrocortisone for the treatment of breast carcinoma with apocrine features: a case report illustrating this new paradigm.
      . Regarding the molecular intrinsic subtypes, the molecular apocrine-like tumors have been associated with poor prognosis. Among patients included in the EORTC10994 study, 93 had a molecular apocrine subtype, and the 5-year recurrence-free survival was 59.2%. Most of them had a ductal histology
      • Bonnefoi H
      • MacGrogan G
      • Poncet C
      • Iggo R
      • Pommeret F
      • Grellety T
      • et al.
      Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes.
      .
      Cystic adenoid TNBC correspond to about 0.1 - 1% of breast cancers
      • Gillie B
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      • Xiao P.
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      . The biphasic pattern of myoepithelial and epithelial cells suggests cystic adenoid TNBC origins from ductal epithelium
      • Gillie B
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      • Asarian A
      • Xiao P.
      Adenoid cystic carcinoma of the breast with distant metastasis to the liver and spleen: a case report.
      . They usually occur in postmenopausal women between the fifth and sixth decades of life
      • Dhouib F
      • Kallel M
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      • Fourati N
      • Siala W
      • Chaabane K
      • et al.
      Adenoid cystic carcinoma of the breast.
      ,
      • Romeira D
      • Cardoso D
      • Miranda H
      • Martins A.
      Adenoid cystic carcinoma: triple negative breast cancer with good prognosis.
      , and despite typically triple-negative phenotype, these tumors usually have a very good prognosis, with rare cases of metastasis in previous literature
      • Gillie B
      • Kmeid M
      • Asarian A
      • Xiao P.
      Adenoid cystic carcinoma of the breast with distant metastasis to the liver and spleen: a case report.
      • Dhouib F
      • Kallel M
      • Mnejja W
      • Fourati N
      • Siala W
      • Chaabane K
      • et al.
      Adenoid cystic carcinoma of the breast.
      • Romeira D
      • Cardoso D
      • Miranda H
      • Martins A.
      Adenoid cystic carcinoma: triple negative breast cancer with good prognosis.
      • Mhamdi HA
      • Kourie HR
      • Jungels C
      • Aftimos P
      • Belbaraka R
      • Piccart-Gebhart M.
      Adenoid cystic carcinoma of the breast - an aggressive presentation with pulmonary, kidney, and brain metastases: a case report.
      . In our study, however, we identified 4 patients with metastatic cystic adenoid carcinoma. Treatment is not consensual
      • Dhouib F
      • Kallel M
      • Mnejja W
      • Fourati N
      • Siala W
      • Chaabane K
      • et al.
      Adenoid cystic carcinoma of the breast.
      ,
      • Romeira D
      • Cardoso D
      • Miranda H
      • Martins A.
      Adenoid cystic carcinoma: triple negative breast cancer with good prognosis.
      , and considering its rarity, little is known about the role of systemic treatment. Our results suggest some activity of cytotoxic chemotherapy, since three patients received neoadjuvant chemotherapy, with two of them presenting a partial response.
      Finally, medullary pattern of non-special type invasive carcinoma was the second most common histology in our sample, comprising 14 cases. Medullary pattern was previously described as medullary carcinoma, atypical medullary carcinoma or carcinoma with medullary features, representing less than 1% of breast cancer cases. These tumors were recently sub-classified as a special pattern of invasive carcinoma among the non-special type
      • Lakhani S
      • Ellis I
      • Schnitt S
      • Tan P
      • van de Vijver M.
      WHO classification of tumours of the breast.
      . Actually, medullary pattern represents a spectrum of diseases that has as its hallmark an immune-enriched microenvironment. They are usually triple-negative high-grade tumors as observed in our cohort, in which most of these tumors were grade 3 (85.7%), with a median Ki67 index of 55
      • Lakhani S
      • Ellis I
      • Schnitt S
      • Tan P
      • van de Vijver M.
      WHO classification of tumours of the breast.
      . Despite presenting histological characteristics that suggest an aggressive disease, medullary pattern carcinomas have a better prognosis when compared to invasive carcinomas of no special type. This fact is attributed to the presence of a rich infiltrate of tumor-infiltrating lymphocytes (TIL), frequently observed in these tumors. Indeed, our results showed a pathologic complete response rate of 100% among the 7 patients who received neoadjuvant chemotherapy.

      Conclusion

      Our data confirm that TNBC have diverse behavior, response to treatment, and survival according to histological type. Lobular and metaplastic TNBC are more aggressive diseases, with many patients experiencing disease progression during neoadjuvant chemotherapy or recurrence after treatment for early disease. Medullary pattern and apocrine TNBC, otherwise, had much better outcomes. Despite the controversy regarding the benefits of neoadjuvant treatment for metaplastic TNBC, we believe that neoadjuvant treatment could be offered for these patients, especially if upfront surgery is not readily available. Molecular studies are warranted to further characterize each of the diseases and guide the development of better therapies.

      Clinical Practice Points

      • Due to the rarity of special histological types of triple-negative breast cancer (TNBC), many knowledge gaps still need to be clarified about these diseases. Treatment standards that are established for breast carcinoma of no special type frequently do not apply properly for the special types. Each special histological type seems to have particularities regarding the molecular background and disease behavior. Consequently, responses to treatment strategies can be highly distinct. Our results showed that metaplastic and lobular TNBC have a high aggressiveness, and response to cytotoxic chemotherapy is poor. On the other hand, medullary pattern carcinomas had a pathologic complete response rate of 100% after neoadjuvant chemotherapy. Although no benefit was observed with chemotherapy for apocrine carcinomas, patients with these tumors had favorable outcomes. Adenoid cystic carcinomas had an intermediate prognosis in our cohort. Additional studies focusing on molecular features of the special histological types of TNBC are warranted to guide the rational development of better treatment strategies.

      Disclosures

      RCB has received grant, financial support for educational programs and symposia, and personal fee for expert testimony from AstraZeneca, grant from Novartis, financial support for attending symposia from Roche, and personal fee for expert testimony from Ache, outside the submitted work. FAC has received fee non-continuing medical education services from BMS, Novartis and AstraZeneca. GNM has received financial support for educational programs or symposia from Bayer Schering Pharma and Roche. PBCP has received financial support for educational programs or symposia from Merck. LT has received grant from Novartis, personal fee for expert testimony from MSD, Lilly, Novartis and Genomic Health, fee for non-continuing medical education services from Lilly, Novartis, Pfizer, Roche and Libbs, travel support from Pfizer, Roche, Libbs and United Medical, outside the submitted work. MSF has received financial support for educational programs and symposia from Roche, Pfizer and Lilly, outside the submitted work. All other authors have no disclosure/ conflict of interest.

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