Are more likely to be diagnosed clinically rather than mammographically than ER-positive cancers
Are more likely to be diagnosed as interval cancers between mammograms:
However, intrinsic differences in the density of breast tissue among women diagnosed with TNBC may also explain these differences in presentation
Pathologic characteristics:
TNBC are usually:
High grade
The most common histology is:
Infiltrating ductal carcinoma:
Although a rare histologic subtype:
Medullary carcinoma:
Is generally triple negative
TNBCs can exhibit geographic necrosis, a pushing border of invasion, and a stromal lymphocytic response (Table)
Immunophenotypic and pathologic features of triple negative breast cancer
An uncommon subgroup of TNBCs:
Is defined histopathologically as metaplastic:
However, this is a diverse group of cancer types ranging from squamous to stromal in nature
By definition:
TNBC lacks immunohistochemical (IHC) expression of the:
ER, PR, and HER2
Since these three biomarkers represent the only known approved targets for breast cancer treatment:
Considerable effort has been made to better understand other biologic forces driving TNBC
Molecular classification of TNBC:
The triple-negative clinical phenotype:
Mostly comprises the basal-like molecular subtype:
Although triple-negative and basal breast cancers are not synonymous and there is substantial heterogeneity within TNBCs:
As examples, in one study of utilizing DNA and RNA profiling of TNBCs:
Four stable subtypes were identified:
Luminal androgen receptor
Mesenchymal
Basal-like immunosuppressed
Basal-like immune-activated
In another study, 172 triple-negative tumors based on IHC staining were correlated with gene expression profiles that defined the basal subtype:
Only 71% of TNBCs were assigned the basal subtype
In a converse analysis (where subtype was identified and correlated with IHC staining) of 160 tumors:
77% of basal tumors were triple negative by IHC
Other evidence from copy number variation and mutational analyses has also suggested wide variability and breadth of clonal spectra in TNBC
Basal breast cancer:
Is characterized by the genomic expression of the “basal cluster,”:
A unique cluster of genes that includes the epidermal growth factor receptor (EGFR, also called HER1), basal cytokeratins 5/6, c-Kit, the proliferation cluster, and low expression of the hormone receptor- and HER2-related genes
Separate subtypes of TNBC have been characterized by gene expression, including:
Two basal-like subtypes (BL1 and BL2)
Immunomodulatory
Mesenchymal
Mesenchymal stem-like
Luminal androgen subtypes
Additional subtypes that have been characterized include:
Claudin-low
Interferon-rich subtypes
Gene expression analysis:
Has also revealed that the tumor suppressor gene p53 (TP53) and several DNA repair genes:
Particularly the breast cancer susceptibility genes (BRCA):
Are either mutated or aberrantly expressed in TNBC
These molecular features may have implications for chemotherapy sensitivity to platinum and other directly DNA-damaging agents
Taken together, these studies have produced mixed results with varying conclusions among the different investigators:
None has reached the level of providing clinical considerations at present
TNBC accounts for approximately 15% of breast cancers diagnosed worldwide:
Which amounts to almost 200,000 cases each year
Compared with hormone receptor-positive breast cancer:
TNBC is more commonly diagnosed in women younger than 40 years:
In one study, there was a twofold higher attributable risk of TNBC in women under 40 years compared with women over 50 years (odds ratio [OR] 2.13, 95% CI 1.34-3.39) [5].
In addition, TNBC appears to be relatively more common among Black women compared with White women (OR 2.41, 95% CI 1.81-3.21)
Risk factors associated with the diagnosis of TNBC include:
Positive BRCA mutation status:
Up to 20% of patients with TNBC harbor a breast cancer susceptibility gene (BRCA) mutation:
Particularly in BRCA1
By contrast, less than 6% of all breast cancers are associated with a BRCA mutation
Given this finding, any patient with triple-negative disease should be offered a referral to a genetic counselor to discuss BRCA germline testing:
Moreover, any patient age 60 years or younger with TNBC should undergo BRCA germline testing
Race / ethnicity:
Several population-based studies have found that African American women have a higher risk of TNBC compared with White women:
However, African American women can certainly have ER-positive and / or HER2-positive disease:
Testing their tumors for these markers is essential
Premenopausal status:
Premenopausal status has been associated with increased incidence of TNBC diagnosis as compared with postmenopausal status
As with African American women:
Premenopausal women can frequently have ER-positive and / or HER2-positive disease:
Testing their tumors for these markers is essential
Other factors:
Studies have suggested relationships between other factors such as obesity and a young age of first pregnancy with an increased risk of TNBC:
While breastfeeding and parity may be associated with lower risks:
However, these factors are less well validated and rarely factor into clinical considerations
Is a term that has historically been applied to cancers that:
Lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)
TNBC:
Tends to behave more aggressively than other types of breast cancer
Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes):
There are no approved targeted treatments available:
Although immunotherapy (in combination with chemotherapy) is available for those with advanced TNBC:
That expresses programmed cell death ligand 1 (PD-L1)
One definition “triple-negative” to mean cancers that have:
Less than 1% expression of ER and PR as determined by immunohistochemistry (IHC), and that are, for HER2, either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not amplified), according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines
Although the basic principles of diagnosis and management of TNBC are similar to those of breast cancer in general:
Many aspects, including risk factors, molecular and pathologic characteristics, natural history, and chemotherapy sensitivity, are unique to TNBC
Today, the U.S. Preventive Services Task Force (USPSTF) posted a draft recommendation statement on screening for breast cancer.
The USPSTF now recommends that all women get screened for breast cancer every other year starting at age 40 years.
More research is needed on whether or not women with dense breasts should have additional screening with breast ultrasound or magnetic resonance imaging and on the benefits and harms of screening in women older than 75 years
Fisher B, Anderson S, Bryant J, et al. Twenty-year followup of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med. 2002;347(16):1233-1241.
Litiere S, Werutsky G, Fentiman IS, et al. Breast-conserving therapy versus mastectomy for stage I-II breast cancer: 20 year followup of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13(4):412-419.
Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med. 2002;347(16):1227-1232.
The second generation of laryngeal preservation trials were published in 2003
The RTOG 91–11 trials:
Showed that both concomitant and neo-adjuvant chemoradiotherapy with cisplatin:
Resulted in no statistically significant differences in survival compared to radiotherapy alone:
However, laryngeal preservation was highest with concomitant chemoradiotherapy (84%) compared to neo-adjuvant chemoradiotherapy (72%) and radiotherapy alone (67%)
On the other hand, concomitant chemoradiotherapy resulted in significantly worse acute toxicity compared to induction and chemotherapy and radiotherapy alone
Reference:
Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New England Journal of Medicine 2003; 349: 2091–8.
Is characteristically spontaneous, unilateral, uni-ductal or bloody
Physiologic discharge:
Is nonspontaneous, bilateral, and milky
The most common causes for pathologic nipple discharge are:
Benign:
Intraductal papillomas
Duct ectasia
In a patient with a pathologic nipple discharge:
And the presence of abnormal clinical findings on imaging or physical exam:
Is associated with increased risk of malignancy:
38% vs. 2%
Contemporary workup for nipple discharge includes:
Mammography
Evaluation of the retroareolar region with ultrasound
Patients with normal findings on mammography, ultrasound, and physical exam:
Can be further evaluated with breast MRI, as it is highly sensitive and specific for cancer
A patient with abnormalities in the physical exam and in imaging (ultrasound or mammography:
Would need surgical intervention even with a negative breast MRI
Surgical management of nipple discharge includes:
Excision of a single duct or central duct apparatus:
Depending on the number of ducts involved
References
Li GZ, Wong SM, Lester S, Nakhlis F. Evaluating the risk of underlying malignancy in patients with pathologic nipple discharge. Breast J. 2018;24(4):624-627.
de Paula IB, Campos AM. Breast imaging in patients with nipple discharge. Radiol. Bras. 2017;50(6):383-388.
Yilmaz R, Bender O, Celik Yabul F, Dursun M, Tunaci M, Acunas G. Diagnosis of nipple discharge: value of magnetic resonance imaging and ultrasonography in comparison with ductoscopy. Balkan Med J. 2017;34(2):119-126.
Current consensus guidelines from the American Society of Breast Surgeons:
Do not recommend contra lateral prophylactic mastectomy (CPM):
For women with sporadic breast cancers
A Cochrane review of eight studies evaluating patients who underwent CPM concluded that:
While CPM reduces risk of contralateral breast cancer:
It is not associated with improved survival
Reasons for not recommending CPM include:
A low estimated risk of cancer in the contralateral breast:
2% to 6% over 10 years
Increased complication rates
Studies showing that CPM does not improve survival or recurrence from the index cancer
References
Lostumbo L, Carbine N, Wallace J, Ko H. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2004(4):CD002748.
Boughey JC, Attai DJ, Chen SL, et al. Contralateral prophylactic mastectomy consensus statement from the american society of breast surgeons: additional considerations and a framework for shared decision making. Ann Surg Oncol. 2016;23(10):3106-3111.
Is the most commonly used technique for guiding excision of nonpalpable lesions in the breast:
It may also be used to localize a clipped axillary node
However, WL may require coordination of scheduling in the operating room and radiology, result in patient discomfort, and the wire may potentially become dislodged or malpositioned
Localization devices that do not require wires are increasing in popularity to overcome some of these issues:
For both techniques, the localization device, such as a radioactive seed, is implanted via mammographic or sonographic guidance prior to surgery:
Although initially used mostly for non-palpable breast lesions, use of these techniques is increasing in localization of lymph nodes, especially after neoadjuvant chemotherapy
The use of neoadjuvant chemotherapy in node-positive breast cancer patients:
Can result in clinical downstaging of the axilla:
Allowing for de-escalation of axillary surgery with use of sentinel node biopsy rather than axillary dissection
Marking previously biopsied nodes and excision at time of breast surgery:
Has been shown to reduce false negative rates of sentinel node biopsy:
6.8% vs. 19.8% without excision of clipped node
This is recommended by the National Comprehensive Cancer Network
Radioactive seed placement has not been shown to interfere with the isotope utilized in sentinel node mapping
References
1. Lovrics PJ, Goldsmith CH, Hodgson N, et al. A multicentered, randomized, controlled trial comparing radioguided seed localization to standard wire localization for nonpalpable, invasive and in situ breast carcinomas. Ann Surg Oncol. 2011;18(12):3407-3414.
2. Cox CE, Russell S, Prowler V, et al. A prospective, single arm, multi-site, clinical evaluation of a nonradioactive surgical guidance technology for the location of nonpalpable breast lesions during excision. Ann Surg Oncol. 2016;23(1):3168-3174.
3. Caudle AS, Yang WT, Mittendorf EA et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial. JAMA Surg 2015;150(2):137-143.
4. Boughey JC, Ballman KV, Le-Petross HT et al. Identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with node-positive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance). Ann Surg. 2016;263(4):802-807.
5. Diego EJ, McAuliffe JF, Soran A, et al. Axillary staging after neoadjuvant chemotherapy for breast cancer: a pilot study combining sentinel lymph node biopsy with radioactive seed localization of pre-treatment positive axillary lymph nodes. Ann Surg Oncol. 2016;23(5):1549-1553.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial was a randomized, double-blind, placebo-controlled trial of postoperative tamoxifen treatment (10 mg BID) for breast cancer patients with ER+ tumors and histologically negative lymph nodes.
Patient population:
2644 patients with ER+ histologically node-negative breast cancers
Patients were administered the drug for at least 5 years
After 15 years of follow-up, compared with placebo:
Tamoxifen-treated patients were found to have benefited irrespective of age, menopausal status, or ER concentration for:
RFS:
78% tamoxifen vs. 65% placebo
OS:
71% tamoxifen vs. 65% placebo
A multivariate analysis indicated that all subgroups investigated showed benefit from tamoxifen treatment:
This included a reduction in rate of treatment failure at local and distant sites, a reduction in rate of incidence of new tumors in the contralateral breast, and a reduction in loco-regional recurrence after lumpectomy and breast irradiation
While NSABP B-14 is known for establishing tamoxifen as an effective adjuvant therapy in ER+, node-negative patients:
Disease-free survival and OS were found to decrease over the 15-year follow-up in a subset of patients originally thought to have a favorable prognosis:
These findings prompted researchers to find a way to optimize treatment in this group:
Thus, the NSABP conducted the B-20 trial to evaluate the value of adding chemotherapy to tamoxifen for treatment regimens in ER+, node-negative patients:
Results from the B-20 trial after a 12-year follow-up demonstrated a significant improvement in disease-free survival with the addition of chemotherapy to tamoxifen when compared to tamoxifen alone
References
1. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med.1989;320(8):479-484.
2. Fisher B, Jeong JH, Bryant, Anderson S, Dignam J, Fisher ER, et al. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet. 2004;364(9437):858-868.
3. Newman LA, Mamounas EP. Review of breast cancer clinical trials conducted by the National Surgical Adjuvant Breast Project. Surg Clin N Am. 2007;87(2):279-305.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 