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Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 327-332

Pattern of distant metastasis in molecular subtypes of carcinoma breast: An institutional study

Department of Radiotherapy, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. J Poddar
Department of Radiotherapy, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_177_17

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 » Abstract 

BACKGROUND: Molecular subtypes of carcinoma breast show a particular pattern of distant metastasis, the knowledge of which can help to diagnose and intervene early in the course of the disease. AIM: The aim of this study was to investigate and establish an association between the molecular subtypes of carcinoma breast and the pattern of distant metastasis. SETTINGS AND DESIGN: Single arm, retrospective study. MATERIALS AND METHODS: Totally 400 patients of carcinoma breast (Stage I and II) were selected who were treated between January 2010 and December 2013. All these patients were treated with the standard treatment protocol for breast cancer. The estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER-2) Neu status, and Ki-67 were done, and patients were classified into luminal A/B, HER-2 enriched, luminal/HER-2, and triple-negative subtypes. All patients were followed up until December 2015, and the pattern of local failure as well as distant metastasis was correlated with the molecular subtypes. RESULTS: A total of 143 patients developed distant metastasis and local recurrence. Bone was the most common site of metastasis overall. It was the most common type of metastasis in luminal A/B (53.3%) and luminal-HER (57.1%). Brain metastasis was most common in HER-2-enriched subtype (30.3%), whereas liver was the most common site of metastasis in HER-2-enriched subtype (45.45%). The incidence of brain metastasis was comparatively lower in luminal A/B subtype. Local recurrence was most common in HER-2-enriched subtype. The results were statistically significant for lung metastasis and local recurrence (with P = 0.004 and 0.047, respectively). CONCLUSION: A strong association exists between the molecular subtypes and the site of distant metastasis in breast cancer which can be used for greater vigilance to detect site-specific distant metastasis beforehand.

Keywords: Carcinoma breast, molecular subtypes, pattern of metastasis

How to cite this article:
Kunikullaya S U, Poddar J, Sharma A D, Patel S. Pattern of distant metastasis in molecular subtypes of carcinoma breast: An institutional study. Indian J Cancer 2017;54:327-32

How to cite this URL:
Kunikullaya S U, Poddar J, Sharma A D, Patel S. Pattern of distant metastasis in molecular subtypes of carcinoma breast: An institutional study. Indian J Cancer [serial online] 2017 [cited 2021 Aug 1];54:327-32. Available from: https://www.indianjcancer.com/text.asp?2017/54/1/327/219555

 » Introduction Top

Carcinoma breast is one of the earliest malignancies known to humanity as it is described in ancient documents which dates back to the 6th century, when it was considered as “Divine punishment.”[1] The treatment has evolved over centuries, from radical mastectomy to lumpectomy, from classical chemotherapy drugs to doxorubicin and taxane-based chemotherapy and hormonal therapy regimens and introduction of highly sophisticated radiation techniques for adjuvant radiotherapy. In the late 1970s, the understanding of metastatic pattern gave this disease the status of a systemic illness. Since then, a lot of research has been dedicated for combating the systemic spread of this malignancy. Steven Paget's “Seed and Soil” hypothesis for metastasis was a milestone in the study of malignant diseases, which proposes that specific organs are predisposed targets for the secondary growth as they express certain genes to invade specific organs.[2] Recent studies have reported that the genes responsible for the aggressiveness of the tumor are different from those involved in its capacity of homing, surviving, and proliferating in a particular organ.[3]

Carcinoma breast presents with a wide spectrum of clinical, pathological, and genetic characteristics resulting in a considerable variation in prognosis. Perou et al. first described the molecular subtypes of carcinoma breast in the year 2000.[4]

This classification of carcinoma breast into molecular subtypes was a breakthrough discovery, as it gave way to the hypothesis that molecular subtypes have the clinical and biological significance and they show a particular pattern in the local and distant spread. The various subtypes show different response to chemotherapy drugs, hormonal therapy, and overall prognosis, due to the difference in the gene expression pattern. A particular subtype preferentially metastasizes to a particular distant site.[5] The refinement of the classification, the risk of relapse and the prediction of response to multidisciplinary treatment for early breast cancer was the major theme of the 14th St. Gallen International Breast Cancer Consensus Conference 2015.[6] The paradigm shift from modified radical mastectomy to breast conservation surgery and the increasing debate regarding irradiation of the axilla and the internal mammary lymph nodes has led to considering the molecular subtypes, for predicting the pattern of spread. To improve the prognosis in cases of advanced malignancy, we need to target our interventions very early in the course, toward both the seed (cells which disseminate from the primary tumor) and metastatic soil (the target homing organ).

With this background knowledge, we evaluated the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2)/Neu expression data of the primary breast cancer patients; first to classify them into the molecular subtypes, then to study the organ-specific metastasis. We wanted to validate our results with other studies as a better and beforehand understanding the patterns of metastatic spread may influence adjuvant therapy and surveillance decisions to determine appropriate investigations and therapies, once metastasis is diagnosed. If a likely site of metastasis is known, then a more specific search for metastasis can be done during follow-up and the patients can be explained about the development of any alarming signs which should be brought under attention. The following analysis is presented: 5 years cumulative incidence of distant metastasis among patients of luminal A/luminal B, luminal/HER-2, HER-2 enriched, and triple-negative (TN) subtypes.

 » Materials and Methods Top

Totally 400 patients of Stage II and III carcinoma breast without any evidence of clinical or radiological distant metastasis at diagnosis were studied retrospectively in the period of January 2010–December 2011 and were followed up until December 2015. The data were collected from hospital records. All the diagnostic investigation reports were noted, for example, mammosonography and biopsy. Work up for metastasis was reviewed which included chest X-ray for lungs metastasis, ultrasound of abdomen and pelvis for liver metastasis, and bone scan (for Stage III) for bony metastasis. Computed tomography (CT) scan of thorax, brain, or abdomen was done if clinically indicated. Any patient who had metastasis at the time of initial diagnosis was excluded from the analysis.

All the patients included in the study were of pathological Stage II and III (AJCC staging system) which was ascertained from the surgical histopathological report. All patients had underwent modified radical mastectomy as the primary treatment modality followed by adjuvant chemotherapy and radiotherapy. Adjuvant therapy was in the form of four cycles of doxorubicin and cyclophosphamide-based chemotherapy followed by postoperative radiotherapy (45 gray in 20 fractions). The radiotherapy was followed by taxane-based chemotherapy for four cycles. It was followed by hormonal therapy for patients who were ER- and PR-receptor positive.

We evaluated the ER, PR, and HER-2/Neu expression data of the primary breast cancer patients; first to classify them into the molecular subtypes, then to study which specific subtype showed what organ-specific metastasis. The ER, PR, and HER-2/Neu status of all the patients were noted and the patients were accordingly classified into luminal A/B, HER-2/Neu enriched, TN, and luminal/HER. Breast cancer molecular subtypes were classified according to a gene expression profile validated immunohistochemical (IHC) surrogate panel as follows: luminal A (ER positive, PR positive, and Ki-67 ≤14%), luminal B (ER positive, PR positive, and Ki-67 >14%), luminal/HER-2 (ER positive, PR positive, and HER-2 positive), HER-2 enriched (ER negative, PR negative, and HER-2 positive), TN (ER negative, PR negative, and HER-2 negative). IHC staining was performed for ER, PR, HER-2, and Ki-67 by fully automated machine VENTANA BENCHMARK XT. ER positivity and PR positivity were defined as any positive nuclear staining (≥1%) using Alldred scoring system, and HER-2-positive cases were defined by positive membranous scoring. For HER-2/Neu, IHC score of 3+ or IHC score of 2+ plus fluorescent in situ hybridization with amplification ratio ≥2.0 was considered to be positive.

The patients were followed up for the development of any local recurrence and distant metastasis. Distant relapse was defined as relapse of breast cancer, beyond the limits of the ipsilateral breast, regional lymph nodes, or chest wall. Distant metastatic sites were categorized as follows: brain (including the central nervous system [CNS], pituitary gland, leptomeningeal spread, choroid, and frontal sinus), liver, lung (including lymphangitic carcinomatosis and pleural metastasis), and bone (including bone marrow). The pattern of failure was correlated with the molecular subtypes.

Bone scan and X-rays were used for the diagnosis of bone metastasis. CT scan of thorax and abdomen were used for the diagnosis of lung and liver metastasis. Magnetic resonance imaging or CT scan of the brain is used for diagnosis of brain metastasis.

[Table 1] shows the different subtypes classified in this study.
Table 1: The different subtypes classified in this study

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The P value was calculated and P < 0.05 was considered to be statistically significant. All calculations were performed using SPSS 16.0 (Statistical Package for the Social Sciences version 16 produced by the International Business Machines Corporation, Armonk, New York, USA) software.

 » Results Top

All the patients were infiltrating ductal carcinoma of the breast of AJCC Stage II and III. Mean age of the patients was 54 years. Of 400 patients studied, 143 patients developed distant metastasis and local recurrence at the end of the evaluation, while 257 remained disease-free.

Out of 400 patients studied, 104 were luminal A/B type (26%), 148 were HER-2 enriched (37%), 84 were luminal-HER type (21%), and 64 were TN type (16%).

Out of 143 patients who developed recurrence or distant metastasis, thirty patients were luminal A/B (21%), 66 were HER-2 enriched (46%), 28 were Luminal/HER (19.7%), and 19 (13.3%) were TN.

The site of metastasis along with the molecular subtypes is tabulated in [Table 2].
Table 2: The site of metastasis in relation to the molecular subtypes

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The important observations for the results were as follows:

  • Bone was the most common site of metastasis in all the molecular subtypes. The vertebrae were the most common bones involved by metastasis
  • Bone was the most common site in luminal A/B (53.3%) and luminal HER variety (57.1%)
  • Brain was the most frequent site of metastasis in HER-2-enriched variety (30.3%)
  • Liver metastasis was most frequent in HER-2-enriched variety (45.45%)
  • The incidence of brain metastasis was comparatively lower in luminal A/B variety
  • The overall incidence of bone metastasis was 46.8%, of liver metastasis was 39.8%, of lung metastasis was 21.6%, and brain metastasis was 26.5%. The overall incidence of local recurrence was 19.5% and was highest in HER-2-enriched subtype.

The overall incidence of lung metastasis and local recurrence was found to be statistically significant and was calculated using Chi-square test. The P value for lung metastasis was 0.004 (P< 0.05) and for local recurrence was 0.047 (P< 0.05) and was found to be statistically significant. The P value for bone metastasis was 0.394 which was not statistically significant and that for liver metastasis which was 0.58. The P value for brain metastasis was 0.68. The level of significance was kept at 0.05.

Each molecular subtype was analyzed to find out whether the frequency of metastasis to different sites, observed in each of the variety, was significant or not.

The analysis of luminal A/B subtype is shown in [Table 3].
Table 3: The analysis of luminal A/B subtype with different sites of metastasis

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Out of the patients of luminal A/B subtype (n = 30), 53% had bone metastasis, 33% had liver metastasis, 6% had lung metastasis, and 20% had brain metastasis. Nearly 13% of patients developed local recurrence. The association of luminal A/B subtype with distant metastatic sites was calculated and the P = 0.0002 which was statistically significant.

[Table 4] shows the analysis of Her-2-enriched variety with different sites of metastasis.
Table 4: The analysis of human epidermal growth factor receptor-2 enriched variety with different sites of metastasis

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Out of the patients of HER-2-enriched variety who developed metastasis (n = 66), 42% developed bone metastasis, 45% developed liver metastasis, 30% had lung metastasis and brain metastasis each, and 27% developed local recurrence. The association of HER-2-enriched subtype with distant metastatic sites was calculated and P = 0.1006 which was statistically insignificant.

[Table 5] shows the analysis of luminal/HER variety with different sites of metastasis.
Table 5: The analysis of luminal/HER variety with different sites of metastasis

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Out of the patients of luminal/HER subtype who developed metastasis (n = 28), 57% developed bone metastasis, 39% developed liver metastasis, 7% developed lung metastasis, 29% developed brain metastasis, and 21% developed local recurrence. The association of Luminal/HER subtype with distant metastatic sites was calculated and the P = 0.0009 which was statistically significant.

[Table 6] shows the analysis of TN variety with different sites of metastasis.
Table 6: The analysis of triple-negative variety with different sites of metastasis

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Of all the TN patients who developed metastasis (n = 19), 37% of patients had bone metastasis, 32% had liver metastasis, 37% had lung metastasis, 21% had brain metastasis, and none had local recurrence.

The association of TN subtype with distant metastatic sites was calculated and the P = 0.0458 which was statistically significant.

 » Discussion Top

According to the American Cancer Society, more than 230,000 new cases of invasive breast cancer are diagnosed every year in women and over 2300 in men. In 2015, approximately 40,000 women and 440 men died of breast cancer. Although the screening programs and advancements in treatment have improved the overall survival in carcinoma breast, still this disease remains unconquered.

Carcinoma breast is considered a systemic disease because even in the early stages, it can metastasize to distant sites and treatment strategies directed only to control the primary tumor do not suffice. The tumor cells appear to disseminate and circulate much before the primary tumor becomes clinically detectable. In some patients, the latency period between the initial treatment and recurrence is very long, which suggests that the tumor cells may both alter and respond to the host environment, to facilitate and sustain disease progression. Local and distant metastasis in breast carcinoma patients makes the overall prognosis dismal and overall survival poor. There are multiple prognostic and predictive factors for carcinoma breast, for example, tumor size, tumor grade, lymph node involvement, age at diagnosis, lymphovascular invasion, hormonal receptor status, etc., which determine the prognosis as a whole for these patients.[7] Although the predictive and prognostic markers are well known, they cannot predict which site would be affected by metastasis.

Since the time the molecular subtypes of breast carcinoma have been described, various studies have explored the clinical and pathological association regarding response to the systemic treatment and the recurrence risk. The knowledge of molecular subtypes of cancer and the genetic analysis is limited. Still a definite pattern of the metastasis can be elicited which can make further investigations and follow-up focused and easier.

A large study was conducted by Kennecke et al. on 3726 patients of carcinoma breast. The patients were classified into various molecular subtypes. For example, luminal A, luminal B, luminal/HER-2, HER-2 enriched, basal-like, and TN nonbasal. Distant metastatic sites were identified as the brain, liver, lungs, and bones. Association between the molecular subtype and site of distant metastasis was found. On multivariate analysis, this study showed that the molecular subtypes were associated with significant differences in the pattern of distant metastasis. Bone was found to be the most common site of distant metastasis except in basal type. Compared to luminal A/B type, luminal/HER, and HER-2 enriched had higher incidence of brain, liver, and lung metastasis.[8]

Smid et al. explored if the reported molecular subtypes in breast cancer have a predilection for any specific organ for relapse. They tried searching for molecular pathways involved in this mechanism of distant spread. They found that bone relapse was highest in the luminal subtypes and was comparatively lesser in the basal subtype. The reverse was true for the incidence of lung and brain relapse. They concluded that the five major molecular subtypes in breast cancer are quite different in terms of their potential to metastasize to distant organs and share biological characteristics with the target homing organs which paves the pathway to their preferred metastatic site.[9]

The results which we obtained in our study were in accordance with these studies. Bone was the most common site of distant metastasis in all subtypes and the incidence was lesser in TN variety. Luminal/HER and HER-2 enriched variety had higher incidence of brain and liver metastasis. Brain was the most common site of metastasis in HER-2 enriched variety, and the liver metastasis was common in HER-2-enriched subtype.

Kuru et al. conducted a study on 470 patients of carcinoma breast, T1-3 tumors with distant relapse after surgery. Prognostic factors were compared as solitary skeletal, multiple skeletal, and visceral metastases. The study showed that bone was the most common site of metastasis and bone metastasis carried a better prognosis than visceral metastasis.[10] In our study, the patients often presented with bone metastasis. Patients, in whom, bone was the first site of recurrence had a longer survival than those who presented first with visceral metastasis. Solitary bone metastasis has a better prognosis than multiple bone metastasis.

Park et al. observed in a study of 313 carcinoma breast patients that distant recurrence is one of the most important risk factor in overall survival and it is related to the biological signature of the tumor. They found out the correlation between the molecular subtypes and the pattern of distant recurrence and found that the incidence of distant recurrence is associated with the molecular subtypes. Brain metastasis was common in HER-2 enriched and luminal/HER variety.[7]

This finding was in accordance with the result obtained in our study. HER-2 over amplification tends to provide aggressiveness to the tumor. As HER-2 positive breast cancer is a relatively aggressive subtype, patients with HER-2 positive tumors might have an increased incidence of brain metastasis. HER-2 expressing tumors may have a predilection for brain metastases.[11],[12]

Kallioniemi et al. demonstrated that HER-2 positive disease is associated with a characteristic pattern of metastatic spread and those with overexpression of HER-2 gene metastasize three times more often to brain.[13]

An important drawback of our study was the unavailability of trastuzumab to all the HER-2/Neu-enriched patients as it is expensive and beyond the reach of all the patients. This would have impacted the rate of distant metastasis in this group of patients. Trastuzumab has proved to be beneficial in HER-2-positive patients and has reduced the relapse risk in these patients.[14],[15],[16] However, in few randomized trials, of metastatic HER-2-positive breast cancer, trastuzumab showed no effect on the incidence of isolated CNS metastases.[17] The incidence of brain metastasis in patients with HER-2-positive metastatic tumor who received trastuzumab has been reported to be 25%-34%. The probable reason could be that CNS represents a sanctuary site, due to the presence of the blood–brain barrier (BBB). The BBB prevents the penetration of molecules which have a molecular weight >200 daltons. Trastuzumab has a molecular weight of around 145,000 daltons. Hence, it may not be able to cross the BBB, as its levels are found to be low in cerebrospinal fluid, of patients who are on this drug. Although trastuzumab therapy does not appear to provide protection for brain metastasis, in the absence of trastuzumab therapy, other visceral metastasis may develop earlier, in the course of the disease, and other visceral organ failure may cause the death of the patient before the development of brain metastasis. This can be a plausible hypothesis for an increase in the incidence of brain metastasis in the patients of HER-2 on trastuzumab.[17]

Patients with TN breast cancer are also predisposed to increased risk of developing brain metastasis. Lin et al. found that in TN breast cancer, the development of brain metastasis was relatively earlier and the median survival after the development of metastasis was relatively less.[18] These patients develop brain metastasis relatively earlier as compared to other subtypes and usually, the brain is the first site of metastasis in these patients.[19] It does not appear that the high rate of CNS involvement is due to a sanctuary effect, but rather to the lack of effective therapy, in general, for this aggressive subtype of breast cancer. New treatment strategies are required.

 » Conclusion Top

From the results obtained in our study, we conclude that the molecular subtypes of carcinoma breast are distinct in respect of tumor aggressiveness and response to treatment per se. All subtypes behave differently in terms of their ability to metastasize.

All the simultaneously detected metastasis (synchronous), occurring in different target organs were included in our study. An important point to note is that the site of distant relapse did not show any association with prognosis, that is, association of a molecular subtype with a site of relapse does not correlate with the prognostic outcome.

Bone metastasis is most common among all and carries overall better prognosis as compared to visceral metastasis. We observed that most common molecular subtype was HER-2 enriched. The overall incidence of metastasis and local recurrence was also higher in HER-2 enriched variety. Brain metastasis has the poorest prognosis among all the types of metastasis which was also highest in HER-2 enriched type. Analysis of breast cancer subtypes and different clinicopathological parameters is important because it provides valuable prognostic and predictive information.

Patients who are anticipated to develop visceral metastasis may be asked for participation in clinical trials to receive novel adjuvant therapy. Therefore, identification of prognostic factors for disease-free survival and the prediction of the development of solitary and multiple skeletal and visceral metastases, among breast carcinoma patients, is of great importance.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Yalom, Marilyn, Alfred A. Knopf A history of the breast. New York: p. 234. ISBN 0-679-43459-3.  Back to cited text no. 1
Psaila B, Lyden D. The metastatic niche: Adapting the foreign soil. Nat Rev Cancer 2009;9:285-93.  Back to cited text no. 2
Norton L, Massagué J. Is cancer a disease of self-seeding? Nat Med 2006;12:875-8.  Back to cited text no. 3
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52.  Back to cited text no. 4
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418-23.  Back to cited text no. 5
Esposito A, Criscitiello C, Curigliano G. Highlights from the 14th St Gallen International Breast Cancer Conference 2015 in Vienna: Dealing with classification, prognostication, and prediction refinement to personalize the treatment of patients with early breast cancer. Ecancermedicalscience 2015;9:518.  Back to cited text no. 6
Park HS, Kim S, Kim K, Yoo H, Chae BJ, Bae JS, et al. Pattern of distant recurrence according to the molecular subtypes in Korean women with breast cancer. World J Surg Oncol 2012;10:4.  Back to cited text no. 7
Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7.  Back to cited text no. 8
Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008;68:3108-14.  Back to cited text no. 9
Kuru B, Camlibel M, Dinc S, Gulcelik MA, Gonullu D, Alagol H. Prognostic factors for survival in breast cancer patients who developed distant metastasis subsequent to definitive surgery. Singapore Med J 2008;49:904-11.  Back to cited text no. 10
Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91:639-43.  Back to cited text no. 11
Leyland-Jones B. Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol 2009;27:5278-86.  Back to cited text no. 12
Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ. Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 1991;49:650-5.  Back to cited text no. 13
Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006;354:2103-11.  Back to cited text no. 14
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr., Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84.  Back to cited text no. 15
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72.  Back to cited text no. 16
Gaedcke J, Traub F, Milde S, Wilkens L, Stan A, Ostertag H, et al. Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol 2007;20:864-70.  Back to cited text no. 17
Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: High incidence of central nervous system metastases. Cancer 2008;113:2638-45.  Back to cited text no. 18
Heitz F, Harter P, Lueck HJ, Fissler-Eckhoff A, Lorenz-Salehi F, Scheil-Bertram S, et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur J Cancer 2009;45:2792-8.  Back to cited text no. 19


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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