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Overview of the Updated NCCN Guidelines on Triple-Negative Breast Cancer
Breast cancer affects about 12.9% of women during their lifetime, with an estimated 281,550 new cases anticipated in 2021. Breast cancer encompasses about 14.8% of all new cancer cases, and the disease will kill 43,600 people in 2021, making up 7.2% of all cancer deaths. Overall, women with breast cancer in the United States experience a 90.3% 5-year survival rate. In general, 63% of new breast cancer cases are localized when diagnosed, 29% have regional lymph node spread, 6% have metastasized, and 2% are unknown or unstaged at diagnosis. While the rate of new breast cancer cases rose slightly at 0.3% on average yearly between 2009-2018, age-adjusted death rates have fallen by an average of 1.3% yearly from 2010-2019.1
A small but aggressive portion of breast cancer cases—about 12% of those diagnosed in the United States from 2012 to 2016—are triple-negative breast cancers (TNBCs). Patients with this cancer type have lower 5-year survival rates of 8% to 16% compared to those with hormone receptor-positive disease.2 TNBCs test negative for progesterone and estrogen receptors, as well as excess HER2 protein. For these reasons, this cancer type is not responsive to hormonal therapies. In addition, the cells can be basal-like, a more aggressive and higher-grade cancer, and most TNBCs have this feature.3 The mortality rate is higher for TNBC patients partly because a greater number of the cancers become metastatic. With fewer treatment options than other breast cancer subtypes, and with TNBC being more resistant to conventional treatment, patients have a worse prognosis.4
Relapse is common in TNBC, including for women with localized disease. Around 25% of those with localized disease will experience relapse with distant metastasis. Overall survival rates for TNBC patients with advanced or stage IV disease is approximately 12 months compared to 36 months for those with ER-positive/PR-positive/HER2-negative disease. In this latter group, 40% of patients survive to at least 4 years vs less than 20% of patients in the TNBC group.3
TNBC is a disease that disproportionately affects non-Hispanic Black women and younger women. Twice as many non-Hispanic Black women are diagnosed with TNBC compared to Hispanic women or non-Hispanic White women. Women younger than 40 years had the highest odds of a TNBC diagnosis, and women aged 75 years or older had the lowest odds.5 There are an estimated 170,000 global cases diagnosed annually. TNBC is the most common subtype of breast cancer for those carrying a BRCA1 gene mutation.3 Up to 20% of women with TNBC have a BRCA mutation, with a higher risk for younger women.6
Staging and Classification
The American Joint Committee on Cancer (AJCC) stages breast cancers based on clinical and pathological staging. Clinical staging is the rating given prior to treatment, based on the clinical exam, biopsy, and imaging studies, with a “c” placed before the staging letters and numbers. The pathological staging is defined by the surgical specimen, with a “p” used before the other staging information.7 The cancer is given a TNM score for staging, from 0-4, with higher numbers indicating larger tumors or more invasive metastasis. Stage 0 is noninvasive, stages I-III are invasive, and stage IV is metastatic (Tables 1 and 2).
The tumors are numbered based on size; a T1 tumor is 2 cm or less, and a T3 tumor is more than 5 cm. A T4 tumor has invaded nearby structures, and Tfd is inflammatory carcinoma. Nodes are numbered 0-3, with N0 showing no cancer in regional nodes, and N1-N3 showing metastasis in the regional lymph nodes. The higher numbers indicate more lymph nodes involved. Metastasis is shown with 0 or 1, where 0 means no distant metastasis, and 1 indicating metastatic breast cancer.7
Breast Cancer Workup
The workup for noninvasive breast cancer should include a history and physical; imaging studies (bilateral mammogram, ultrasound as necessary, and optional breast magnetic resonance imaging [MRI]); a pathology review; and testing for estrogen, progesterone, and HER2 status.8BRCA mutation testing is also recommended, especially for patients younger than 50 years.3 For recurrent or stage IV breast cancer, the workup would include additional imaging, such as a chest computed tomography (CT) with contrast, abdominal and pelvic diagnostic CT with contrast or MRI with contrast, a brain and/or spine MRI if symptomatic or suspicious, a bone scan or sodium fluoride positron emission tomography (PET)/CT, optional fluorodeoxyglucose-PET/CT, and x-rays of symptomatic bones. The patient would also undergo biomarker testing of the tumor from disease recurrence, reevaluation of ER/PR and HER2 status to compare against the primary lesion, and comprehensive germline and somatic profiling to identify potential targeted therapies.8
TNBC Treatment
In addition to surgery and radiation, chemotherapy is often the main treatment for TNBC, particularly when the disease is metastatic. Some patients will receive chemotherapy alone or with pembrolizumab to shrink larger tumors. Chemotherapy and pembrolizumab may also be given in the adjuvant setting to prevent recurrence. Patients with the BRCA mutation may receive poly ADP ribose polymerase (PARP) inhibitors (olaparib or talazoparib) at some point. Patients with advanced TNBC who have already tried two lines of therapy may be offered the antibody drug conjugate sacituzumab govitecan as a potential option.
Per the National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines,8 patients who are cT0, N+, M0 would be treated per the occult primary guidelines. Those with cT1-T3 staging would be considered for preoperative systemic therapy. Benefits of preoperative systemic therapy include possible breast conservation, potentially allowing inoperable tumors to become operable. For TNBC patients, preoperative systemic therapy can provide helpful prognostic information about treatment response on the individual patient level. It also can help identify TNBC patients with residual disease who are at a higher risk for relapse to provide supplemental adjuvant regimens. Preoperative systemic therapy is for operable breast cancer in TNBC patients staged at cT ≥2 or cN ≥1. Systemic therapy is also recommended for inoperable breast cancer in those with cT4 tumors, cN3 nodal disease, bulky cN2 axillary nodes, and inflammatory breast cancer.8
For preoperative and adjuvant therapy, the preferred regimens and category 1 recommendations for TNBC patients are dose-dense doxorubicin/cyclophosphamide followed by paclitaxel; docetaxel/cyclophosphamide; or olaparib (if the patient has BRCA1/2 mutations). High-risk (stage II-III) TNBC patients can receive preoperative pembrolizumab/carboplatin/paclitaxel, followed by preoperative pembrolizumab/cyclophosphamide/doxorubicin or epirubicin, followed by adjuvant pembrolizumab. TNBC patients with residual disease after preoperative therapy with taxane-, alkylator-, and anthracycline-based chemotherapy can receive capecitabin. Other recommended regimens include doxorubicin/cyclophosphamide followed by docetaxel; epirubicin/cyclophosphamide; docetaxel/doxorubicin/cyclophosphamide; or for select patients with TNBC in the preoperative setting, weekly paclitaxel/carboplatin or docetaxel/carboplatin. The guidelines note that including platinum agents as neoadjuvant chemotherapy with TNBC patients is controversial.8
Those with operable tumors but not considering preoperative systemic therapy would receive breast conserving therapy or a total mastectomy, both with surgical axillary staging. Radiation would be considered based on the axillary involvement.8
The NCCN guidelines recommend that TNBC patients who received preoperative systemic therapy could consider receiving capecitabine 6 to 8 cycles as adjuvant systemic therapy after radiation, if their pathological staging is T1-4, N0, or N≥1. Those with T0, N0 would enter surveillance.8
Treating Recurrent and Unresectable TNBC
Only 5% of TNBC patients are diagnosed initially with metastatic disease. Most relapses occur after treating with curative intent. Relapse, when it occurs, is typically within 3 years. TNBC is sensitive to chemotherapy, but these patients are prone to untimely relapse and resistance, which is said to be the triple-negative paradox.3 Patients with recurrent or unresectable (local or regional) or stage IV (M1) disease would remain on systemic therapy until progression or unacceptable toxicity. The preferred regimens for TNBC are anthracyclines (doxorubicin or liposomal doxorubicin); taxanes (paclitaxel); antimetabolites (capecitabine or gemcitabine); microtubule inhibitors (vinorelbine or eribulin); or sacituzumab govitecan, approved for adult patients with metastatic TNBC who received at least two prior therapies, with at least one for metastatic disease. Patients with BRCA1/2 mutations are potential candidates for PARP inhibitor therapy. Platinum therapy is also a preferred therapy for TNBC and BRCA1/2 mutations (carboplatin or cisplatin).
Other recommended regiments include cyclophosphamide, docetaxel, albumin-bound paclitaxel, epirubicin, or ixabepilone. Sequential single agents are preferred by the Guidelines, but they do outline a number of chemotherapy combinations for select patients with high tumor burdens, rapidly progressing disease, and visceral crisis.
If the current line of therapy is not working, the clinician can offer a new line. Patients with the BRCA1/2 mutation could receive olaparib or talazoparib, both category 1 recommendations. TNBC patients with PD-L1 expression may receive pembrolizumab and chemotherapy (albumin-bound paclitaxel, paclitaxel or gemcitabine and carboplatin), as category 1 recommendations. Pembrolizumab and chemotherapy is a preferred first-line therapy, but it can be used for second and subsequent lines if the therapy has not been previously used. About 1 in 5 patients with TNBC have the PD-L1 protein.9 At some point, the patient and clinician may decide not to continue systemic therapy and move to supportive care instead.
Summary of Guideline Changes and Supporting Data
The Guidelines went through multiple updates in 2021. The latest version is 8.2021, published on September 13, 2021.8 Summary of changes from the last 3 updates are detailed below.
Sacituzumab govitecan: The 8.2021 update moved sacituzumab govitecan from “other recommended regimens” to “preferred regimens” for systemic therapies for recurrent unresectable (local or regional) or stage IV (M1) disease. It also modified footnote “g” on that page, which said that this treatment was for adult patients with metastatic TNBC who received at least two prior therapies, adding with at least one line for metastatic disease. The change came from the phase 3 ASCENT trial,10 which compared sacituzumab govitecan to single-agent chemotherapy of the physician’s choice, in patients with relapsed or refractory metastatic TNBC. Their primary end point was progression-free survival (PFS) in patients without brain metastases. The trial included 468 patients randomly assigned to sacituzumab govitecan or chemotherapy. All patients were pre-treated with taxanes. The results showed a median PFS of 5.6 months (95% CI, 4.3-6.3; 166 events) for the sacituzumab govitecan arm, and 1.7 months (95% CI, 1.5-2.6; 150 events) in the chemotherapy army (hazard ratio [HR] for disease progression or death, 0.41; 95% CI, 0.32-0.52). The median overall survival (OS) was 12.1 months (95% CI, 10.7-14.0) for the sacituzumab govitecan group, and 6.7 months (95% CI, 5.8-7.7) for the chemotherapy arm. In the sacituzumab govitecan arm, 35% patients had an objective response compared to 5% in the chemotherapy group. Each group experienced treatment-related adverse events grade 3 or higher and three deaths in each group due to adverse events, but this was not related to sacituzumab govitecan treatment. Authors noted that the benefit in the sacituzumab govitecan arm was seen in all clinical and prespecified subgroups, including patients who received previous treatment with PD-1 or PD-L1 inhibitors.
Atezolizumab and albumin-bound paclitaxel: Also in the 8.2021 update, the Guidelines removed the option for atezolizumab and albumin-bound paclitaxel as additional targeted therapies and associated biomarker testing for recurrent unresectable (local or regional) or stage IV (M1) disease. They removed the footnote to assess PD-L1 expression biomarker status on tumor-infiltrating immune cells to identify candidates for atezolizumab plus albumin-bound paclitaxel. Atezolizumab received accelerated approval for TNBC, but phase 3 post-approval studies yielded negative clinical trial results. Atezolizumab and paclitaxel were evaluated for first-line therapy in the IMpassion131 trial for advanced TNBC. Primary results were published in August 2021.11 The study included 651 randomized patients who had no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy. They were randomized 2:1 to atezolizumab or placebo, both with paclitaxel until disease progression or unacceptable toxicity. They were stratified by PD-L1 status and other factors. The study’s primary end point was PFS, with OS as a secondary end point. The researchers found that at the primary PFS analysis, the addition of atezolizumab to paclitaxel did not improve PFS in the PD-L1 positive population (HR, 0.82; 95% CI, 0.60-1.12; P=.20; median PFS 6.0 months with atezolizumab-paclitaxel vs 5.7 months with placebo-paclitaxel). The combination in the PD-L1-positive population was associated with more favorable unconfirmed best overall response rate (63% vs 55% with placebo), and the median duration of response was 7.2 months vs 5.5 months, respectively. The final OS results showed there was no difference between the arms (HR, 1.11; 95% CI, 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel vs 28.3 months with placebo-paclitaxel in the PD-L1-positive population). The results for the intent-to-treat population were consistent with the PD-L1-positive population. Researchers concluded that the combination did not improve PFS or OS over the paclitaxel alone.
Olaparib: The 7.2021 update corrected footnote “g” on the preoperative/adjuvant therapy regimen page, to consider adding adjuvant olaparib for 1 year, for those who have germline BRCA1/2 mutations and have TNBC if 1) ≥pT2 or ≥pN1 disease after adjuvant chemotherapy, or 2) residual disease after preoperative chemotherapy. The phase 3 double-blind randomized OlympiA trial involved HER2-negative early breast cancer patients with BRCA1/2 mutations who received local treatment and neoadjuvant or adjuvant chemotherapy. The 1836 patients were divided 1:1 to 1 year of olaparib or placebo, with a primary end point of invasive disease-free survival. At a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib arm and 77.1% in the placebo arm (95% CI, 4.5-13.0; HR for invasive disease or death, 0.58; 99.5% CI, 0.41-0.82; P<.001). The 3-year distant disease-free survival was 87.5% in the olaparib arm and 80.4% in the placebo arm (95% CI, 3.0 to 11.1; HR for distant disease or death, 0.57; 99.5% CI, 0.39-0.83; P<.001). Researchers found that olaparib was associated with fewer deaths than the placebo group (59 and 86, respectively) (HR, 0.68; 99% CI, 0.44-1.05; P=.02). There were no excess or serious adverse events of special interest to the researchers. They concluded that olaparib was associated with significantly longer survival free of invasive disease or distant disease compared to placebo.10
The 5.2021 update added a footnote (then marked “j”) to say: the patients in OlympiA trial did not receive capecitabine, thus there is no data on sequencing or to guide selection of one over the other. Subsequent updates kept the wording but the footnote is now “i.” Olaparib dosing information was added on the preoperative/adjuvant therapy regimen page.
Pembrolizumab: The 6.2021 update offered additional options for HER2-negative disease. The Guidelines added this option for high-risk TNBC: preoperative pembrolizumab + carboplatin + paclitaxel, followed by preoperative pembrolizumab + cyclophosphamide + doxorubicin or epirubicin, followed by adjuvant pembrolizumab. They added footnote “j”: High-risk criteria include stage II-III TNBC. The use of adjuvant pembrolizumab (category 2A) may be individualized,” along with the reference to the New England Journal of Medicine publication from 2020.10 The dose and schedule were added to the Guidelines as well. This phase 3 trial randomly assigned patients 2:1 with previously untreated stage II or III TNBC to neoadjuvant therapy with four cycles of pembrolizumab plus paclitaxel and carboplatin, or to placebo plus paclitaxel and carboplatin. Both groups then received an additional four cycles of pembrolizumab or placebo, plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. The patients received surgery and then adjuvant pembrolizumab or placebo, with a primary end point of pathological complete response at surgery and event-free survival in the intention-to-treat population.
The first interim analysis of 602 randomized patients showed a 64.8% pathological complete response (95% CL, 59.9-69.5) for the pembrolizumab group and 51.2% (95% CI, 44.1-58.3) in the placebo group (95% CI, 5.4-21.8; P<.001). After a median follow-up of 15.5 months (range, 2.7-25.0), 58 of 784 patients (7.4%) in the pembrolizumab group and 46 of 390 patients (11.8%) in the placebo group experienced disease progression precluding them from definitive surgery, experienced local or distant recurrence or a second primary tumor, or died from any cause (HR, 0.63; 95% CI, 0.43-0.93). The incidence of treatment-related adverse events grade 3 or higher across all treatment phases was 78.0% in the pembrolizumab group and 73.0% in the placebo group, with death in 0.4% (3 patients) and 0.3% (1 patient), respectively. Authors concluded that the patients in the pembrolizumab treatment arm had a significantly higher pathological complete response compared to the placebo arm.
Discussion
There is still a significant unmet need for treating TNBC to offer durable remissions and more effective therapies. Therapeutic additions in the last few years include targeted therapies like PARP inhibitors (olaparib and talazoparib) which inhibit tumor growth and can be used by patients with BRCA mutations. Pembrolizumab is an option for some patients, but atezolizumab failed in its post-approval trial. More research is needed to understand what drives TNBC’s growth and metastasis, and to find better therapies for this hard-to-treat population.
References
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