Triple-Negative Breast Cancer,TNBC

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Triple-Negative Breast Cancer, TNBC

  • Triple-negative breast cancer (TNBC) is usually an invasive ductal carcinoma with cells that lack estrogen and progesterone receptors and do not have an excess of HER2 protein on their surfaces. These types of breast cancers tend to spread more quickly and do not respond to hormone therapy or drugs that target HER2.
  • 10-24% of all invasive breast cancer are TBNC
  • The majority of tumors in BRCA1 mutation carriers are triple negative
  • Triple-negative tumors generally do not respond to receptor targeted treatments. Depending on the stage of its diagnosis, triple negative breast cancer can be particularly aggressive, and more likely to recur than other subtypes of breast cancer.
  • The five-year survival rate for TNBC is around 77 percent versus 93 percent for other breast cancer types. 
triple-negative breast cancer

Triple-negative breast Cancer is a  subtype of breast cancer generally diagnosed based upon the lack of, three “receptors” known to fuel most breast cancers: estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2). Triple-negative tumors generally do not respond to receptor targeted treatments. Depending on the stage of its diagnosis, triple negative breast cancer can be particularly aggressive, and more likely to recur than other subtypes of breast cancer. Triple-negative breast cancer is more common in younger women. It’s more common in women who have tumors that are BRCA1mutations. We know that the younger African-American women have a significantly increased likelihood of having triple-negative breast cancer.

TNBC is a diagnosis of exclusion, based on lack of ER and PR, and of HER2 overexpression or gene amplification ), but generally 10–24% of invasive breast cancers fall into this category. TNBCs are typically high-grade tumors, although low-grade tumors do occur. Furthermore, although most TNBCs are of ductal (not otherwise specified) type, other rarer tumors (for example, metaplastic, medullary and adenoid cystic tumors) may be triple negative and these may have a better prognosis than the usually poor one of TNBCs in general. Most molecular-profiling studies suggest that although most TNBCs (about 70%) fall into the basal-like breast carcinoma subtype(BLBC), the remainder consist of a variety of molecular subtypes that are biologically distinct.  These findings suggest that TNBC is not a single disease but includes additional tumor types, making it a heterogeneous entity. 

Germ like mutations are seen in TNBC(15%) and they  germline mutations that are within  the BRCA1 and BRCA2 genes

TNBC  and BLBC relationship

TNBC also has subtypes. The most common is the Basal Like breast carcinoma- some time the name is used interchangeably. As the name suggests, the BLBC subtype expresses genes normally expressed in cells of the normal, non-luminal (basal), myoepithelial layer of the breast duct and lobular system including cytokeratins 5, 14 and 17, smooth muscle actin, EGFR, P-cadherin, and CAV1 and CAV2. These basal-like features are found in 2–20% of all invasive breast cancers. Most BLBCs are triple negative; however, about 5% of ER-positive tumors and between 6% and 35% of HER2-positive tumors show a basal-like gene-expression profile. Basal-like features have also been demonstrated in the in situ component of invasive BLBCs.

Among approximately 500 women evaluated in the Carolina Breast Cancer Study, those with basal-like tumors (defined as ER-negative, PR-negative, HER2-negative, CK 5/6-positive, and/or HER1-positive) were more likely to be African-American (prevalence of 26% vs 16% in non–African-Americans) and premenopausal (24% vs 15% postmenopausal). These investigators observed a particularly high prevalence of basal-like tumors among premenopausal, African-American women compared to postmenopausal African-American women and non–African-American women of any age (39% vs 14% and 16%, respectively. These findings are consistent with several large-scale, population-based studies indicating that triple-negative breast cancers are more likely to occur among premenopausal women of African-American descent

BLBCs share many other features that are also associated with TNBCs. Typically, they are grade 3, ductal carcinomas with a high mitotic count, high apoptotic rate, geographic or central tumor necrosis (and/or fibrosis), a pushing border of invasion, and a stromal lymphocytic response. Several of these characteristics, including hormone-receptor negativity, high grade, medullary-like histology, lymphocytic infiltrate, TP53 mutations, EGFR expression, HER2 negativity, characteristic copy number aberrations, and X-chromosome inactivation patterns, have been termed ‘BRCAness’ because of their similarity to tumors that develop in BRCA1 mutation carriers. BLBCs express proliferation-associated genes (for example, Ki67, PCNA, and cyclin A) at high levels, and up to 75% of BLBCs show TP53 gene mutations and/or nuclear accumulation.] Expression of p63 is also upregulated in BLBCs. Decreased expression and loss of heterozygosity (LOH) of the tumor-suppressor gene Rb1 has also been described in BLBCs, leading to upregulation of the cyclin-dependent kinase inhibitor p16, and a worse prognosis than those without Rb1 LOH. The small heat-shock protein α-basic-crystallin is expressed in about half of all BLBCs and has been associated with poor survival;  overexpression of α-basic-crystallin transforms immortalized human mammary epithelial cells in vitro, via the MEK/ERK pathway, and increases cell migration and invasion.

Apart from lacking estrogen (ER) and progesterone(PR) receptors and no excess of HER2 protein on their surfaces, TNBC has many pathology and molecular features that by itself make it very aggressive tumors with poor prognosis.  Markers such as cytokeratin 5, 14 and 17, and the EGFR HER1.  They also have high expression of genes associated with proliferation (Ki67 and TOP2A), high levels of cyclin E, and low levels of cyclin D1. About 50% of TNBCs have aberrant p53 as detected by immunostaining or mutational analysis,  and/or expression of the p53 homolog p63.  Many of these features are also associated with a poor prognosis in breast cancer. These number of positive markers may also TBNC more responsive to a variety of targeted therapies and offers an alternative to personalized treatment based on the tumor molecular profile.

TNBC and the BRCA1 Mutations

The majority of tumors in BRCA1 mutation carriers are triple negative. By contrast, the frequency of expression in tumors from carriers of BRCA2 germline mutations does not differ significantly from sporadic tumors. BRCA1-associated breast cancers are triple-negative and express a high proportion of basal-like cytokeratins (CK5, 14, 17), as well as P-cadherin and HER1/EGFR. The BRCA1 tumor-suppressor gene, originally identified in 1994 by positional cloning on chromosome 17q21, is a multifocal protein in many normal cellular functions including DNA repair, transcriptional regulation, cell cycle checkpoint control, and ubiquitination.

What are the common results of the biopsy?

Once the tumor is obtained, it will be examined in the laboratory by a pathologist.  This is very important to confirm the results of the biopsy and to provide further information on cancer.  Some of the results of the biopsy, commonly, include the following:

Histological type: assignment of histological type is based on the type of cells that comprise the tumor. Breast cancers form in tissues of the breast, usually the ducts or the lobules. The main histological types of breast cancer are ductal carcinomas and lobular carcinomas. The histopathological examination will also classify cancer as invasive or non-invasive. Non-invasive cancers are also called cancer in situ

Grade: Assignment of the grade is based on the heterogeneity of tumor cells, the architectural structure of the tissue they form and the frequency of mitosis (cell division) of tumor cells. A well-differentiated tumor (grade 1) has low heterogeneity of cells, preserved architectural structure, and few mitoses. An undifferentiated tumor (grade 3) has high heterogeneity, loss of architecture and many mitoses. A moderately differentiated tumor (grade 2) is in between grade 1 and grade 3. The lower the grade, the better the prognosis.

When systemic treatment is planned before surgery, the biopsy results should include hormone receptor* status and HER2 status. When no systemic treatment is planned before surgery, these can be determined in the tumor (and/or the lymph nodes) after their removal by surgery.

Hormone receptor status for estrogen and progesterone: Tumor cells can present receptors to estrogen and receptors to progesterone on their surface or inside the cell. Cells of some tumors present a high level of receptors. This means that their growth and multiplication are stimulated by hormones. Tumors with a high level of estrogen receptors (ER+)* and/or progesterone receptors (PR+) have a better prognosis than tumors lacking estrogen receptors (ER-) and/or lacking progesterone receptors (PR-).

HER2 status:  HER2 is a cell surface protein present in about 20% of breast cancer cases. HER2 is involved in the growth and migration of cells.

Multigene expression profiles: the quantification of the expression of distinct sets of genes expressed by the tumor can also be performed on the biopsy. Such multigene signature analyses are not routinely performed but can help to predict the risk of recurrence and the likelihood of benefit from chemotherapy.

Ki-67 labeling index: Ki-67 is a protein found in the nucleus of cells when they are dividing but not when they rest. Ki-67 labeling index indicates the percentage of cells in which Ki-67 can be found. Analyzing the proportion of dividing cells is a method to determine the level of proliferation of the tumor. Highly proliferating tumors grow faster and have a worse prognosis than slowly proliferating tumors, but at the same time, highly proliferating tumors are more sensitive to chemotherapy.

Oncotype DX is a 21-tumor gene expression assay designed to predict the need for chemotherapy based on patient scores from 0 to 100. Those with a score of 26 to 100 are found to benefit from the addition of chemotherapy to endocrine therapy. However, patients with a score of 0 to 10, defined as a low risk of recurrence, derive minimal to no benefit from added chemotherapy. The benefit of added chemotherapy has been uncertain for patients with intermediate risk (11-25)

How Is Triple-Negative Breast Cancer Treated?

treatment TNBC

Triple-negative breast cancers have a relapsing pattern that is very different from hormone-positive breast cancers: the risk of relapse is much higher for the first 3–5 years, but drops sharply and substantially below that of hormone-positive breast cancers afterward. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exist, although the absolute relapse and survival rates differ across subtypes. Triple-negative breast tumors have been characterized by several aggressive clinicopathologic features including onset at a younger age, higher mean tumor size, higher-grade tumors, and, in some cases, a higher rate of node positivity

Think of cancer cells as a house. To get inside to destroy the cancer, we must bypass three locks on the front door: estrogen, progesterone, and HER2. If your cancer tests positive for any of these three locks, which are known as receptors, then doctors have a few keys they can use to get inside the cell to destroy it. If you have triple-negative breast cancer, it means those three locks aren’t there. So the keys doctors usually use won’t work. Fortunately, chemotherapy is still an effective option.

The five-year survival rate for TNBC is around 

77 percent versus 93 percent for other breast cancer types. 

Often, patients first need to have the lump removed (a lumpectomy) or the entire breast removed (a mastectomy). Then they have chemotherapy treatments to target any cancer cells that can’t be seen—cells remaining in the breast or that may have spread into other parts of the body. Sometimes doctors recommend chemotherapy before surgery to shrink the cancer.

Lumpectomy
With lumpectomy, a surgeon removes the lump from your breast. He or she also checks nearby lymph nodes (the little oval-shaped organs that are part of your immune system) to make sure the cancer hasn’t spread. The surgery takes an hour or two, and most women spend the day at the hospital, but there’s usually no need to stay overnight.

Mastectomy
For a mastectomy, your surgeon removes the breast, and checks the nearby lymph nodes to make sure the cancer hasn’t spread. Some women choose to have breast reconstruction during the same surgery.

Radiation
Lumpectomies are usually followed by radiation therapy. This is where high-energy radiation is given to your breast to kill any remaining cancer cells. It usually takes about 20 minutes per day. Most women go in four to five days a week for about six weeks. You’ll see a radiation doctor to have this done.

Chemotherapy
Cells from the cancerous lump may have spread somewhere else in your body. They’re so small the doctors can’t see them, and they don’t show up on any of the tests. But they could grow until you have a new tumor somewhere else in your body. So the goal of chemotherapy is to kill those little cancer cells wherever they may be. Chemotherapy really lowers the chance that your cancer will come back

chemo for tnbc

The overall poor prognosis of patients with TNBC and/or BLBC and their tendency to relapse with distant metastases indicate a definite need for effective systemic therapies for this disease. Chemotherapy is currently the mainstay of systemic treatment for these patients because hormonal and HER2-directed therapies are not effective.

 Neoadjuvant chemotherapy  studies indicate that TNBCs and BLBCs respond well to anthracycline-based or anthracycline and taxane-based chemotherapy.  Several studies have shown higher rates of pathologic complete response (pCR) to such treatments in TNBC, BLBC and HER2-enriched subgroups compared with luminal tumors. Unfortunately, despite higher response rates, relapse rates are high in patients who do not achieve a pCR, resulting in a worse overall survival in the BLBC and HER2-enriched groups than in patients with luminal tumors.

On exposure to doxorubicin and 5-fluorouracil, luminal cell lines repressed a large number of cell cycle-regulated and proliferation-associated genes, whereas BLBC cell lines repressed genes that were involved in differentiation These studies highlight the challenges of moving to an era in which drugs are used rationally based on accurate, validated predictive markers. 

Despite high proliferation rates and TP53 mutation rates, TNBC seems not to show increased sensitivity to taxanes (compared with non-TNBC) in the metastatic setting. In one study in patients with advanced disease, the response rate and time to treatment failure following paclitaxel monotherapy was not different in patients with TNBC versus other tumor types; however, overall survival was reduced in patients with TNBC.

Retrospective data suggest that regimens that include antimetabolites (for example, cyclophosphamide, methotrexate and 5-fluorouracil [CMF]) may be more effective in TNBC than in other tumor types (although not necessarily more effective than anthracyclines and taxanes. In a neoadjuvant study, TNBCs had the highest response rates to CMF compared with other breast cancers (65% for TNBC versus 51% for HER2-positive tumors and 40% for luminal tumors). In one adjuvant study, patients with BLBC responded better with adjuvant CMF than without, but no such benefit was seen for patients with non-BLBCs.[37] Another study, the MA.5 trial, showed overall superiority for adjuvant cyclophosphamide, epirubicin and 5-fluorouracil (CEF) compared with CMF; however, CMF seemed to outperform CEF in patients with BLBC determined by IHC profile. Although interesting, these data require prospective confirmation before subtype should be used to choose specific chemotherapy regimens.

Mounting preclinical evidence suggests that tumors with a dysfunctional BRCA1 pathway have increased sensitivity to DNA crosslinking agents such as platinum compounds. Clinical data are scant and mainly retrospective but also suggest that BRCA1-associated breast cancers, TNBCs, and BLBCs are sensitive to platinum agents. In one retrospective study of neoadjuvant therapy for breast cancer in BRCA1-mutation carriers, 10 of 12 (83%) patients treated with cisplatin monotherapy had a pCR compared with <25% of the 90 patients treated with other regimens. Although 5-year disease-free survival and overall survival were worse for patients with TNBCs compared with other tumor types, the neoadjuvant response rates were higher (88% versus 51%). Response rates for patients with advanced disease were also higher for patients with TNBCs (41% versus 31%), progression-free survival (PFS) was improved, and there was a trend for superior survival in patients with TNBC

Targeted Therapies and Immunotherapies

Although sensitive to chemotherapy, early relapse is common and a predilection for visceral metastasis, including brain metastasis, is seen. Targeted agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly (ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.

PARP Inhibitors are a family of nuclear enzymes involved in the detection and repair of DNA damage. PARPs are critical enzymes in cell proliferation and are differentially upregulated in many cancers including TNBC and BRCA1-associated and BRCA2-associated tumors. Loss of BRCA1 or BRCA2 is thought to lead to increased dependence on PARP for DNA repair, and preclinical data indicate that BRCA1 and BRCA2 defective cells are markedly sensitive to PARP inhibitors. Olaparib is currently being studied in TNBC and in combination with a range of different cytotoxic and other agents; however, a trial of single-agent olaparib in BRCA1-associated or BRCA2-associated breast and ovarian cancer as well as TNBC and sporadic ovarian cancer did not find activity in the TNBC subset.

The angiogenesis inhibitor bevacizumab, which targets VEGF, is being actively investigated in patients with TNBC following positive results from the E2100 and AVADO trials of bevacizumab in combination with a taxane in patients with metastatic breast cancer. The majority of patients in the E2100 trial were HER2-negative and subgroup analysis showed that patients with ER-negative or PgR-negative disease (who were largely triple negative) benefitted considerably from the addition of bevacizumab to paclitaxel therapy.

EGFR Inhibitors.   TNBC and BLBCs express EGFR in up to 72% of cases. Clinical trials in TNBC and/or BLBC. These include ongoing randomized studies of ixabepilone with or without cetuximab (NCT00633464), and of cisplatin with or without cetuximab (NCT00463788). Data so far suggest that EGFR inhibitors have low efficacy in patients with TNBC when used alone but may improve the efficacy of other agents. In one small study, 12 patients with metastatic TNBC were treated with a taxane in combination with cetuximab; nine of the 11 assessable patients responded although three patients developed brain metastasis during treatmen

Src Inhibitors Activity and expression of the tyrosine kinase c-src are frequently increased in breast cancers, and this is associated with increased motility and invasiveness. Preclinical data indicate that BLBCs are particularly sensitive to inhibition of scr kinase. However, the antitumor activity of the dual abl/src kinase inhibitor dasatinib, was modest (<5% responses) when given as monotherapy to heavily pretreated patients with TNBC. Trials of dasatinib and other dual inhibitors (bosutinib and saracatinib) alone or in combination with chemotherapy, are ongoing, although apart from one trial of dasatinib monotherapy (NCT00817531), these are not specifically in patients with TNBC.

Other therapeutic strategies. The range of genetic abnormalities seen in TNBCs and BLBCs  has opened the door to other therapeutic strategies, many of which are being evaluated in clinical trials. These include agents targeting kinases, including mTOR, androgen receptor, TGF-ß, and the TRAIL receptor. It is still too early to assess the clinical efficacy of these strategies in TNBC and BLBC.

There are numerous ongoing late-stage studies investigating Roche’s Tecentriq (atezolizumab) in combination with chemotherapy in the neoadjuvant or untreated metastatic settings, which highlights the potential of programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint inhibitors in combination regimens. This provides hope for TNBC patients, especially those whose tumors have sufficient infiltrating lymphocytes, which have been shown to respond better to immunotherapies.

There is compelling evidence to suggest that immunotherapies may have their greatest potential earlier in the treatment course, before a patient’s immune system is compromised. Although it is unlikely that monotherapy with checkpoint inhibitors will see a future in this setting, given the lack of demonstrated activity, the combination of the PD-L1 inhibitor Tecentriq with chemotherapy holds more promise. Earlier this month, Roche announced that its Phase III IMpassion130 study of Tecentriq plus chemotherapy versus chemotherapy alone had met its co-primary endpoint of progression-free survival (PFS) in PD-L1-positive metastatic patients.

In a different approach, a Phase I/II trial sponsored by Novartis is exploring the ability to improve immune infiltration in TNBC through the combined use of the novel PD-1 inhibitor spartalizumab with LAG525—an inhibitor of another checkpoint target known as lymphocyte-activation gene 3 (LAG-3). This method aims to render the tumour microenvironment less immunosuppressive, and therefore may enhance the activity of PD-1 blockade. Pre-clinical studies have demonstrated synergistic anti-tumor activity with this approach, but it remains to be validated in the clinic.

Immunotherapy is also being explored in TNBC in combination with other agents, including biologics and small-molecule targeted drugs. For instance, combining a PD-1/PD-L1 inhibitor with a poly ADP-ribose polymerase (PARP) inhibitor, such as the Phase Ib combination of Lynparza (olaparib) with Imfinzi (durvalumab), is being explored to assess whether affecting the repair of tumour DNA can improve the response to checkpoint inhibitor therapy. 

Immunomedics’ sacituzumab govitecan is the only conjugate currently being investigated in a Phase III trial for TNBC, and on 18 July, the FDA accepted Immunomedics’ Biologics License Application (BLA) for filing and granted Priority Review, with a Prescription Drug User Fee Act (PDUFA) date of 18 January 2019. If approved, sacituzumab govitecan will provide metastatic patients with another treatment option in the relapsed/refractory setting and hence will not compete with Tecentriq plus chemotherapy regimens that are being studied in the neoadjuvant and untreated metastatic settings.

immu-132

Ladiratuzumab vedotin , shows 29% objective response rate (ORR) at the recommended dose. It is an investigational antibody-drug conjugate or ADC designed to deliver a potent and clinically validated cell-killing, microtubule-disrupting, agent, called monomethyl auristatin E (MMAE) via a protease-cleavable linker, to cancer cells which express the protein LIV-1.  This protein, expressed by most metastatic breast cancers, is also detected on multiple solid tumors including prostate, melanoma, ovarian, uterine, and cervical cancers. A total of 81 patients with LIV-1-expressing metastatic breast cancer were treated with ladiratuzumab vedotin monotherapy given every three weeks. Patients enrolled in the study had received a median of four prior systemic metastatic therapies. Of these patients, 63 were diagnosed with TNBC and 18 had hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. 

Conclusion

Triple-negative breast cancer (TNBC) is usually an invasive ductal carcinoma with cells that lack estrogen and progesterone receptors and do not have an excess of HER2 protein on their surfaces. These types of breast cancers tend to spread more quickly and do not respond to hormone therapy or drugs that target HER2.10-24% of all invasive breast cancer are TBNC. The majority of tumors in BRCA1 mutation carriers are triple negative. TNBC is neither a single disease entity nor a title of convenience, and much more remains to be learned about this intriguing group of diseases. Although conventional chemotherapy has demonstrated efficacy in the treatment of the tumors, this remains a subtype with a poor prognosis and for which we have no known targeted agents. The most promising avenues of investigation include targeting DNA repair with PARP inhibitors, antiangiogenic agents, and identifying unique genetic or environmental risk factors that may provide a basis for prevention.

The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.

Sources:

  • American Cancer Society
  • The National Cancer Institute
  • National Comprehensive Cancer Network
  • American Academy of Gastroenterology
  • National Institute of Health
  • MD Anderson Cancer Center
  • Memorial Sloan Kettering Cancer Center

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