What is triple-negative breast cancer? How is it diagnosed and treated?

What is triple-negative breast cancer?

When the cell membrane lacks the three receptors called estrogen hormone receptor (ER), progesterone hormone receptor (PR) and human epidermal growth factor receptor 2 (HER2), these  receptors  are absent in a breast cancer called  triple-negative breast cancer (TNBC, Triple Negative Breast Cancer) .

Triple-negative breast cancer is less common than other breast cancer types. It accounts for approximately %15 of all breast cancers. However, because breast cancer is so common, triple-negative breast cancer affects many people; considering that approximately 2 million women worldwide are diagnosed with breast cancer each year, triple-negative breast cancer affects at least 200 thousand women annually. It is particularly common in people of African or Hispanic ancestry, young women and those with a BRCA1 mutation . The commonly used breast cancer treatment, hormone therapy, is not used for this type of breast cancer. 

To understand triple-negative breast cancer, it is also necessary to have an idea of other breast cancers.

Figure 1: Types of Breast Cancer

Until the early 2000s, breast cancer was broadly classified into two groups, sensitive and insensitive to estrogen. This knowledge has now changed, and breast cancer has been found, according to the receptors cancer cells do or do not carry on their surfaces—in other words, their biological characteristics—to have 4 main types.

1. Luminal A: Tumors sensitive to estrogen (ER-positive)
2. Luminal B: Tumors weakly sensitive to estrogen and/or also tumors carrying the Her2 receptor (Her2-positive) 
3. Her2-positive: Tumors insensitive to estrogen that carry the Her2 receptor
4. Triple-negative: Tumors without estrogen and Her2 receptors (triple-negative breast cancer, also known as the basal type)

In 2016, according to a study published in Nature, the cell-surface receptor for the hormone prolactin in patients with triple-negative breast cancer may be an important marker for increasing survival and preventing exposure to intensive treatments. This study indicates that triple-negative breast cancer itself also has subclasses with different characteristics.

Conditions that increase the likelihood of triple-negative breast cancer – risk factors

New studies are investigating risk factors for triple-negative breast cancer. The following factors have been found to potentially increase its risk:

• Obesity and inactivity
  Obesity and an increased body mass index raise the risk of triple-negative breast cancer. Causes include inactivity along with an unhealthy diet.
• Hereditary factors
  Individuals with mutated genes inherited from parents (for example, BRCA1 and 2 mutations) have a higher risk of developing triple-negative breast cancer. Whether there is a higher risk can be assessed by reviewing family members’ medical histories.
  - Related topic: What are inherited BRCA1 and BRCA2 mutations? How should carriers manage their risk? 
• Age
  According to some research, age is among the factors affecting the risk of triple-negative breast cancer. Studies suggest that the risk of developing triple-negative breast cancer is higher before menopause than after menopause.
• Race and ethnicity
  Some studies suggest that risks of triple-negative breast cancer differ between racial groups. It occurs more frequently than usual in African-American women and Ashkenazi Jews.

How is triple-negative breast cancer diagnosed?

Diagnosis is no different from that of other breast cancers. Triple-negative breast cancer can be detected with mammography . As with other breast cancers, a person may also notice a lump in their breast and consult a physician. When a lump or growth is detected, the suspicious tissue needs to be collected through a breast biopsy and examined. The pathology report determines whether cancer cells are present. If breast cancer is diagnosed, the tumor tissue undergoes immunohistochemical examination for estrogen-progesterone and Her2 receptors. If these three tumor markers are negative, it is called triple-negative breast cancer.

- Related topic: Breast cancer symptoms and treatment – the DIAGNOSTIC JOURNEY through questions

Triple-Negative Breast Cancer Treatment Methods and Developments

General Approach to Treatment

The approach to treating triple-negative breast cancer varies with disease stage. In advanced disease, the situations in which chemotherapy, immunotherapy and targeted drugs are chosen and their sequence of use have become clearer. Early and regionally advanced disease require more careful treatment planning.

In early stages

Because of its more aggressive biology, triple-negative breast cancer is more likely, even in early stages, to be treated with systemic therapies before and after surgery, the main treatment.

Methods used before surgery to shrink the tumor, improve surgical success and eliminate micrometastases undetectable by imaging are called neoadjuvant therapy . Chemotherapy and immunotherapy are used for neoadjuvant treatment in triple-negative breast cancer.

Treatments used after surgery to reduce cancer recurrence risk are called adjuvant therapy . Based on tumor size, characteristics and spread, protective adjuvant treatments used in triple-negative breast cancer are chemotherapy and immunotherapy.

In advanced stages

Chemotherapy, immunotherapy and targeted drugs are used in advanced triple-negative breast cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are a new treatment option for patients with advanced triple-negative breast cancer carrying a germline (inherited) BRCA1 or BRCA2 mutation (see the relevant FDA approval).

For individuals whose tumors are programmed death ligand 1 (PD-L1)-positive , advanced triple-negative breast cancer has 2 FDA (United States Food and Drug Administration)-approved immunotherapy options. Approximately %20 to %40 of patients with recurrent metastatic triple-negative breast cancer have PD-L1-positive disease; in these patients, Atezolizumab (Tecentriq) and Pembrolizumab (Keytruda), when added to chemotherapy, have demonstrated the ability to improve progression-free survival (PFS*, time living without progression).

A new targeted drug called Sacituzumab Govitecan is suitable for patients with advanced disease who have previously received at least 2 lines of systemic therapy.

A number of ongoing clinical trials aim to provide more and more effective treatment methods for triple-negative breast cancer.

Now let us look at treatment in detail:

Treatment Options for Patients Without Metastasis

Neoadjuvant and adjuvant treatment options for Triple-Negative Breast Cancer are similar to approaches used in other breast cancers.

If the Tumor Is Smaller Than 0,5 cm

Chemotherapy

Node-negative, triple-negative tumors smaller than 0,5 cm generally have a good prognosis (disease course). Therefore, benefit from chemotherapy, which also entails side effects, is unlikely. Tumors between 1 and 5 mm (microinvasive or smaller) also do not require chemotherapy, although it is important not to overlook the possibility of a small benefit.

Adjuvant Chemotherapy

In a study of the natural course of small triple-negative tumors, patients with tumors up to 1 cm who were not treated with adjuvant chemotherapy had 5-year recurrence-free survival of %75-89, while distant recurrence-free survival was %95. Another study suggested recurrence-free survival of %90-93 without chemotherapy. Given the lack of prospective data, administering adjuvant chemotherapy to patients with small tumors has been left to the patient’s and doctor’s decision.

If the Tumor Is Larger Than 0,5 cm

Chemotherapy

Chemotherapy is recommended for patients with tumors larger than 0,5 cm or with Node+ TNBC regardless of tumor size. However, because this type of breast cancer has a higher recurrence rate than others, it is not suitable for targeted treatment options such as endocrine therapy.

Neoadjuvant or Adjuvant Chemotherapy

Neoadjuvant chemotherapy is recommended for patients with regionally advanced cancer or those unsuitable for breast-conserving surgery. Neoadjuvant chemotherapy may also be considered for patients with residual tumor in the 2-3 cm range (T2) who will receive adjuvant treatment.

In a randomized study of the benefit of adjuvant chemotherapy among women with node+ breast cancer, compared with hormone + patients, hormone (-) patients showed more significant outcomes during the 5 years following treatment. These findings emphasize the importance of neo/adjuvant chemotherapy in TNBC patients unsuitable for targeted therapy.

In addition, for high-risk early-stage triple-negative breast cancer, given with chemotherapy as neoadjuvant treatment and then continued after surgery as a single adjuvant agent, the immunotherapy pembrolizumab received FDA approval in July 2021 and entered standard practice.

Preferred Treatment Regimens

Anthracycline-, Alkylator- and Taxane-based chemotherapy options remain standard treatment regimens for TNBC patients; Carboplatin has recently been added. Taxanes and Anthracyclines have important activity in TNBC treatment, but there are no significant data for alkylating chemotherapies.

A study of the disease-free survival (DFS) benefit of taxane-based chemotherapy compared adjuvant Fluorouracil, Epirubicin and Cyclophosphamide (FEC) with FEC followed by Paclitaxel and reported improvement with the addition of Paclitaxel at year 7 (%74 versus %56).

Another study tested Docetaxel and Cyclophosphamide against an Anthracycline/Taxane-based regimen administered over the same duration and suggested that Anthracycline may be beneficial for TNBC. However, non-Anthracycline-based regimens may be suitable for low-risk TNBC patients who are node-negative, have tumors smaller than 1 cm or have cardiac risk.

• Role of Antimetabolite Agents:
  For stage 2 or 3 TNBC patients, neoadjuvant regimens such as Paclitaxel followed by Doxorubicin and Cyclophosphamide (AC-T) or Docetaxel and Cyclophosphamide (TC) are standard. In a study of cases with residual tumor after these, additional adjuvant Capecitabine treatment was reported to be beneficial.
  For stage 1 TNBC patients, adjuvant treatment rather than standard neoadjuvant treatment such as AC-T or TC was considered appropriate. One study suggested that adding antimetabolite agents such as Capecitabine or Gemcitabine to adjuvant chemotherapy in patients who had not received neoadjuvant chemotherapy did not improve overall survival outcomes. Similarly, adjuvant Gemcitabine studies also produced negative results.
  In conclusion, standard Anthracycline- and/or Taxane-based chemotherapy may be preferred as adjuvant treatment in TNBC patients who have not received neoadjuvant therapy.
• Role of Platinums:
  In studies asking whether adding platinum-based chemotherapy should be “standard” for stage 2 or 3 TNBC, this addition to neoadjuvant regimens has been shown to improve pathological complete response rates. However, it has not yet been shown to improve overall survival in patients receiving Anthracycline-, Alkylator- and Taxane-based treatment. 
• Role of Immunotherapy:
  Based on the FDA approval resulting from the study using the Paclitaxel + Carboplatin + Pemrolizumab regimen and the preoperative AC + Pembrolizumab regimen, adding pembrolizumab to neoadjuvant treatment and continuing it after surgery is recommended for stage 2 and 3 TNBC patients receiving neoadjuvant chemotherapy without a contraindication to immunotherapy. Pembrolizumab is the only agent approved for patients in this situation, and studies of other agents continue.
• Role of RARP Inhibitors in BRCA Mutation Carriers:
  Olaparib is generally preferred in these patients, particularly to avoid Capecitabine toxicity. Adjuvant Olaparip is recommended for patients with a BRCA mutation treated surgically who are node+ or have a primary tumor larger than 2cm.

Frequently Asked Questions About Adjuvant and Neoadjuvant Triple-Negative Breast Cancer Treatment

Should pembrolizumab be continued in the adjuvant setting in patients who achieve a pathological complete response (pCR) after neoadjuvant pembrolizumab and chemotherapy? Although we do not know the relative contributions of neoadjuvant versus adjuvant administration, we recommend continuing pembrolizumab in the adjuvant setting, as in the trial, regardless of whether a pCR has been achieved.

Should adjuvant pembrolizumab be given alongside other adjuvant treatments, for example capecitabine or olaparib (in patients with germline BRCA mutations), in patients who do not achieve pCR? Although no data address this question, we recommend concurrent treatment. Smaller studies suggest that combinations of capecitabine and pembrolizumab, and olaparib and pembrolizumab (in other tumor types), have acceptable safety profiles.

Will adding pembrolizumab also improve outcomes in patients treated with a different neoadjuvant regimen? When incorporating pembrolizumab into neoadjuvant treatment, we use the same regimen used in KEYNOTE-522. It is unknown whether the specific neoadjuvant regimen is critical to obtaining potential benefit from pembrolizumab addition, or whether carboplatin can be omitted without compromising long-term outcomes. However, in patients with stage 2 to 3 TNBC receiving an anthracycline-free regimen because of contraindications to that class of agents, we recommend adding pembrolizumab to their neoadjuvant regimens if they have no contraindication to immunotherapy, such as an underlying autoimmune disorder.

How should TNBC patients who started neoadjuvant treatment without pembrolizumab be managed? For this question, while acknowledging that the KEYNOTE-522 data do not address this situation, we favor adding pembrolizumab to the patient’s neoadjuvant regimen as soon as possible.

Should adjuvant pembrolizumab be used in patients who did not receive it with neoadjuvant treatment or who underwent primary surgery? We believe it is reasonable to extrapolate the potential benefit of adding pembrolizumab to patients who have undergone surgery and are receiving adjuvant chemotherapy with a regimen similar to that used in KEYNOTE-522, with stage 2 and 3 TNBC.

Should carboplatin be standard in neoadjuvant treatment for triple-negative breast cancer? The effect of including carboplatin in neoadjuvant regimens for triple-negative breast cancer has long been debated. In a randomized trial among patients with stage 2 to 3 TNBC receiving anthracycline-based chemotherapy, adding carboplatin increased the pathological complete response rate from 46 percent to 60 percent, but did not improve five-year event-free or overall survival. However, the study was not designed to assess survival outcomes. In a separate trial, adding pembrolizumab to a carboplatin-containing chemotherapy regimen improved event-free survival (overall survival results were immature). Based on these data, our preferred regimen for patients with stage 2 or 3 TNBC includes both pembrolizumab and carboplatin.

Treatment Options for Patients With Metastatic Disease

In metastatic TNBC patients, germline testing for BRCA is performed alongside tumor evaluation for PD-L1, and initial treatment depends on the results of these assessments.

Combination chemotherapy may be appropriate for rapidly progressing visceral disease because concern about potential organ dysfunction and a higher probability of response outweigh the increased risk of toxicity. However, it is also important to know that no data show combination chemotherapy improves overall survival compared with sequential single-agent cytotoxic chemotherapy.

Treatment of Patients Without BRCA Mutations

Treatment in PD-L1-Negative Tumors

Single-agent chemotherapy is used in most patients with sporadic, advanced PD-L1-Negative TNBC. In an analysis based on 10 studies comparing platinum-based and non-platinum chemotherapy regimens, the one-year death rate was %46 in the platinum group and %51 in the non-platinum group. Higher-grade toxicities were also observed in the platinum group.

Treatment in PD-L1-Positive Tumors

For these patients, adding an immune checkpoint inhibitor to chemotherapy rather than chemotherapy alone is recommended.

For TNBC patients with a CPS value (the percentage of all cells staining for PD-L1 (tumor cells, lymphocytes, macrophages)) greater than 10 and with PD-L1 expression, the combination of Pembrolizumab and chemotherapy has been approved by the FDA.

Atezolizumab had received FDA approval in combination with Nabpaclitaxel for advanced TNBC patients with PD-L1 staining. However, although benefit in overall and progression-free survival had been shown, approval was withdrawn because the ongoing study did not show an improvement in progression-free survival.

In addition, strategies are being developed for immunotherapy and other approaches in combination with systemic treatment or radiation therapy, and optimization of biomarkers is being investigated to predict immunotherapy response.

Treatment of Patients With BRCA Mutations

An oral PARP inhibitor is recommended for most TNBC patients with a BRCA mutation who have previously received chemotherapy in the neoadjuvant, adjuvant or metastatic setting. However, chemotherapy is recommended if they have received a PARP inhibitor but the disease has recurred, or if they have not previously received chemotherapy.

For PD-L1-positive TNBC patients, the combination of immunotherapy and chemotherapy may also be an alternative treatment, while for PD-L1-negative patients, both platinums and taxanes may be considered suitable chemotherapy options. The American Society of Clinical Oncology has recommended platinums over taxanes.

There are also ongoing studies of PARP inhibitors. For example, a study testing the combination of Veliparib and the alkylating agent Temozolomide observed greater overall response and clinical benefit in patients with BRCA mutations.

Figure 2: Treatment Targets and Important Signaling Pathways in Triple-Negative Breast Cancer

Ongoing Clinical Trials

• In early-stage disease, immunotherapy appears to benefit patients regardless of PD-L1 status (in the I-SPY2, KEYNOTE-522 and IMpassion031 data), and those with high-risk disease benefit most from adding immunotherapy to standard neoadjuvant chemotherapy.
• Phase 3 trials are investigating the efficacy of mitogen-activated protein kinase 1 (MEK) inhibitors, AKT serine / threonine kinase 1 (AKT1) inhibitors, or phosphoinositide 3-kinase (PI3K) inhibitors in combination with chemotherapy and immunotherapy in patients with advanced TNBC.
• The use of androgen receptor (AR) antagonists is being investigated in TNBC patients expressing AR. The Translational Breast Cancer Research Consortium (TBCRC) will soon initiate a trial evaluating enzalutamide (Xtandi, Astellas) versus enzalutamide plus a glucocorticoid receptor antagonist (mifepristone) versus physician’s choice of chemotherapy in patients with advanced AR-positive TNBC.
• Researchers are also reviewing combination immunotherapy in advanced and even early-stage disease. These immunotherapy agents include new drugs targeting proteins such as LAG3 (lymphocyte activation gene 3), TIM3 (T-cell immunoglobulin and mucin domain-containing protein 3), TIGIT (T-cell immunoreceptor with Ig and ITIM domains) and TLRs (Toll-like receptors).
• In early TNBC, estrogen receptor beta (ERβ) expression is associated with high recurrence risk and short overall survival. ERβ is expressed in up to %30 of TNBCs, and in vivo studies have shown that treating ERβ-positive tumors with estradiol causes tumor regression. The phase 2 TBCRC 051 trial is examining estradiol treatment efficacy in advanced TNBC patients expressing ERβ (NCT03941730).
• Studies including KEYNOTE-522 and IMpassion031 have shown an improvement in pathological complete response (pCR) rates with the addition of immunotherapy to standard neoadjuvant chemotherapy.
• In a study based on gene expression analyses of 587 TNBCs, six different TNBC subtypes were identified: BL1, BL2, IM, M, MSL and LAR. Another review reported biological pathways involved in all these subtypes and promising treatment strategies (Figure 2).

Figure 3: Classification of triple-negative breast cancer molecular subtypes, biological pathways active in these types and promising treatments. (EGFR: epithelial growth factor receptor, GF: growth factor, AR: androgen receptor)

What lies ahead for TNBC research?

Over the last 2 years, a series of advances have occurred in TNBC treatment, including PARP inhibitor approvals for BRCA1 / 2 mutation-associated disease, immunotherapy for PD-L1-positive disease, and sacituzumab govitecan-hziy for previously treated metastatic TNBC. With the identification of these effective agents for metastatic TNBC, future studies will focus on investigating their roles in early breast cancer.

What is becoming increasingly clear is the need for biomarkers predicting response. We know mutations in BRCA1 and BRCA2 can help predict who will benefit from PARP inhibitors, and ongoing studies are evaluating other biomarkers to predict PARP inhibitor response. Dr. Nadine Tung published data showing that PARP inhibition also benefits metastatic breast cancer patients with germline PALB2 mutations . In addition, those with somatic BRCA1 / 2 mutations benefit from the PARP inhibitor olaparib (Lynparza, AstraZeneca).

Although PD-L1 positivity predicts immunotherapy benefit in metastatic TNBC, it is far from perfect as a biomarker. Research continues to focus on identifying more robust markers predictive of benefit.

It is important for patients to participate actively in their treatment plan. This plan should include the steps to be taken and what can be done if the cancer does not respond to treatment or begins to spread.

Another important issue during treatment, as we always emphasize, is exercising and eating healthily. A proper diet and exercise help people feel better during treatment.

Survival and the disease course (prognosis) in triple-negative breast cancer vary according to cancer stage at diagnosis, treatment response and other individual factors. Detecting cancer early and treating it effectively naturally increases survival rates.