Clinical Features Of Metastatic Tnbc
Only 5% of patients with TNBC present with de novo metastatic disease. The majority of patients unfortunately relapse following treatment with curative intent. The biological features of TNBC result in a unique clinical phenotype. It is characterized by a propensity for visceral and brain metastases, absence of bone metastases and typically early relapse .
Data from a Canadian breast cancer cohort with 180 TNBC patients showed that these patients were much more likely to develop distant recurrence or death compared to other breast cancer subtypes. The risk of distant recurrence peaked at three years and declined rapidly thereafter. A large cohort study from MD Anderson Cancer Centre identified similar patterns of distant recurrence and death.
TNBC is most commonly associated with visceral metastases including lung, liver and brain. Jin et al identified 433 women with metastatic TNBC and found that 29% of them had 1 or greater brain metastases. Median survival from time of diagnosis of brain metastases in this study was just 7.3 mo highlighting the significant mortality associated with intracranial disease.
Management Of The Breast
NAC downsizes tumors, allowing patients thought to require mastectomy to become BCT candidates. In a meta-analysis that included 11 studies and approximately 5000 patients, Mieog et al reported a 17% decrease in the mastectomy rate for patients receiving NAC. This underestimates the effect of NAC on converting patients to BCT candidates, as most trials lacked a requirement to declare which patients were BCT candidates at diagnosis. In NSABP B-18, surgeons indicated whether a patient was a candidate for BCT before initiation of NAC. For those with tumors â¥5 cm, a population generally not considered optimal candidates for BCT, a lumpectomy was proposed in 3% of patients but was successfully performed in 22% after receipt of NAC. For women with tumors measuring from 2 to 5 cm, NAC improved the BCT rate by 10%.
Identifying Responders To Immunotherapy: Current Status And Future Perspectives
KEYNOTE-522 results prompted a rapid change in clinical practice, leading to the FDA approval of the first immunotherapy agent for early-stage TNBC. This landmark achievement, however, has raised a multitude of scientific questions, requiring a new set of prospective clinical trials.
Besides baseline biomarkers, one established dynamic biomarker, namely the achievement of pCR after neoadjuvant treatment, showed a critical value in KEYNOTE-522. Indeed, a major absolute benefit in terms of EFS was observed among patients not achieving pCR, with a 10% improvement in 3-year EFS for patients receiving pembrolizumab, whereas only a 2% difference was observed in those patients achieving pCR. This finding – together with the results of GeparNuevo showing survival outcomes similar to KEYNOTE-522 with immunotherapy administered only before surgerysupport the experimental testing of strategies to de-escalate adjuvant immunotherapy in patients achieving pCR with chemo-immunotherapy. Nonetheless, until prospective evidence is available, current standards of care should include the adjuvant administration of pembrolizumab to all patients receiving it in the neoadjuvant setting without experiencing concerning irAEs. Moreover, when comparing EFS curves from patients achieving pCR in the two arms, it is important to stress the fact that the addition of pembrolizumab led to more patients achieving pCR, ultimately enriching the population of patients achieving a favorable EFS.
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In Combination With Ddr
Resistance to PARP inhibitors can occur in certain cancer contexts by various mechanisms, including increased HRR capacity and decreased cell cycle progression and DNA replication stress. RAD51 overexpression has been observed in a wide range of human cancers, particularly TNBCs and serous ovarian cancers . Upregulation of RAD51 in BRCA1-defective cells is also associated with resistance to PARP inhibitor . Inhibitors of key mediators of DNA repair and replication, such as ataxia telangiectasia mutated kinase , ataxia telangiectasia and Rad3-related kinase , checkpoint kinase 1 and checkpoint kinase 2 , DNA-dependent protein kinase , and WEE1 kinase have been assessed to determine if they can sensitize tumor cells to treatment with PARP inhibitors, as these inhibitors were found to prevent the accumulation of RAD51 in TNBC .
Phase Iii Impassion 131
The IMpassion-131 study investigated if nab-paclitaxel could be replaced with paclitaxel in combination with atezolizumab in the first-line setting of advanced TNBC. Inclusion criteria were identical to the IMpassion130 trial, but the primary endpoint pertained to investigator-assessed PFS/OS tested first in the PD-L1 positive population. Patients were randomised in a 2:1 ratio to atezolizumab/paclitaxel vs placebo/paclitaxel . In the PD-L1 positive population, there was no significant improvement in the atezolizumab arm with a PFS of 6 mo compared to 5.7 in the placebo arm . There were also no significant differences in PFS in the overall population . In an interim OS analysis, there was no significant differences in OS in the PD-L1 population or the ITT population . The trend towards an improvement in OS was somewhat of a concern for investigators and the medical oncology community. Further analysis demonstrated that patients in both arm had an equivalent exposure to paclitaxel. The reasons for this trend however remain unclear. Speculation includes the potential immune mitigating effects of dexamethasone usage for paclitaxel treatment. This trial resulted in an FDA alert warning against the use of paclitaxel in combination with atezolizumab in TNBC. No new safety signals emerged.
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Can Tnbc Be Prevented
Researchers dont know all the factors that cause triple negative breast cancer. They have identified the BRAC1 gene mutation as one potential cause for triple negative breast cancer. Unfortunately, you cant prevent BRAC1 because you inherit this gene mutation from your parents.
But there are steps that help prevent breast cancers, including TNBC:
- Maintain a healthy weight.
- Exercise on a regular basis.
- Know your family medical history.
- Monitor your breast health. Studies show 95% of women whose breast cancer was treated before it could spread were alive four years after diagnosis.
- Talk to your healthcare provider about genetic testing for the BRCA gene if you have a family history of breast cancer, ovarian cancer, pancreatic or prostate cancer. If you have the BRCA gene, there are steps you can take to prevent breast cancer.
Tnbc Subtyping And Treatment Regimens
In 2011, Lehmann et al. performed gene expression profiling of tumor samples from 587 TNBC patients and divided TNBC into six subtypes: basal-like 1 , basal-like 2 , mesenchymal , mesenchymal stem-like , immunomodulatory , and luminal androgen receptor . They also performed gene profiling and compared existing TNBC breast cancer cell lines, classifying them into six different subtypes, thus providing an accurate cell model for clinical treatment of TNBC .
Table 1 Genomic TNBC subtypes and assignment of TNBC cell lines to subtypes
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What Is Triple Negative Breast Cancer
Triple negative breast cancers are cancers whose cells dont have receptors for:
- the hormones oestrogen and progesterone
- a protein called Her2
Your doctor uses a sample of your cancer to test the cells for these receptors. You might have this test following a biopsy of the cancer, or after surgery to remove it.
A rare type of breast cancer known as basal type breast cancer is usually triple negative. Some women with triple negative breast cancer also have a BRCA1 gene fault. BRCA1 is one of the gene faults that can increase the risk of breast cancer within families.
Some men have triple negative breast cancer but this is very rare. Most men have oestrogen receptors in their cancer cells.
Role Of Platinum Agents
TNBC is often associated with a deficiency in BRCA-driven DNA repair mechanisms, leading to a higher sensibility to interstrand cross-linking agents damaging the DNA, such as platinum agents .
Contrary to data obtained in the metastatic setting, the carboplatin effect was independent of gBRCA status. Patients with gBRCAm had in general a higher pCR rate compared to wild type ones, but the increase in pCR with the addition of carboplatin was more prominent in the wild type cohort . One explanation of the different results could be the single versus combination therapy or the treatment setting.
Results of meta-analyses are consistent . Even though only a few small studies assessed the role of cisplatin , it seems to be as effective as carboplatin in increasing the pCR rate, but with a different safety profile . A head-to-head study of 4 cycles of weekly carboplatin or cisplatin and paclitaxel showed similar pCR rates and outcomes for the 2 compounds. No significant differences were seen in terms of AE .
Many new trials have incorporated carboplatin as part of the standard regimen. Its use is recommended irrespectively of the BRCA status.
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What Does Triple Negative Mean In Terms Of Breast Cancer
Normal breast cells have receptors that respond to hormones such as estrogen and progesterone, which allows them to grow and regress in response to the hormone level. Hormone receptors may or may not be present in breast cancer. About two-thirds of breast cancers are positive and contain these receptors like normal breast cells do. These are less aggressive cancers that are less likely to need chemo and are often treated with hormone therapy and surgery. Radiation may or may not be needed.
HER2/neu , is a protein molecule that has a role in cell proliferation in normal cells. In some breast cancers, this protein is overly produced or positive. For HER2-positive tumors, there a specific medication that targets this protein.
Triple-negative breast cancers are not positive for estrogen receptors, progesterone receptors or HER2 protein. Since these targets are absent in triple-negative breast cancer, chemotherapy is needed, Sun says. Triple-negative breast cancer is often very sensitive to chemotherapy, which, despite the side effects, is an effective treatment that can save lives. Because this is an aggressive cancer, treatment is aggressive also. But there are several ways we can address it.
The Rise Of Immunotherapy For Tnbc
Despite lacking canonical targets for biologic treatment, TNBC is characterized by a relatively high tumor mutational burden compared to other subtypes of BC, a feature which has been linked with increased responsiveness to immunotherapy with immune-checkpoint inhibitors . Indeed, checkpoint inhibition with atezolizumab and with pembrolizumab has been approved for advanced-stage, PD-L1 positive TNBC based on the improvement in outcomes observed when combined with frontline chemotherapy,. Notably, evidence suggest a superior efficacy of ICIs in TNBC when administered early in the disease course, possibly due to the progression of immune escape mechanisms during the advancement of disease,. From this perspective, there was strong rationale for ICI administration to the earliest possible time in the disease course, namely before surgical resection. Results from several randomized trials designed with this purpose are now available, igniting a rapid change of practice in early TNBC.
Table 1 Features and outcomes of the main randomized chemo-immunotherapy trials in early-stage triple negative breast cancer.
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Triple Negative Breast Cancer Meets Its Match With Promising New Treatment
by UT Southwestern Medical Center
One member of a larger family of oxygen sensing enzymes could offer a viable target for triple negative breast cancer , UTSW researchers report in a new study. The findings, published online this week in Cancer Discovery, might offer hope to this subset of patients who have few effective treatment options and often face a poor prognosis.
TNBCso called because it lacks estrogen receptors, progesterone receptors, and overexpression of the growth-promoting protein HER2makes up only 15 to 20 percent of all breast cancers. However, explains Qing Zhang, Ph.D., associate professor in the department of pathology at UTSW and a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research, it’s the deadliest of all breast cancers, with a five-year survival rate of 77 percent compared with 93 percent for other types.
Unlike other cancers which are hormone receptor or HER2 positive, TNBC has no targeted treatments, so patients must rely only on surgery, chemotherapy, and radiation, which are less effective than targeted treatments and can harm healthy tissue.
The opposite was also true: Overexpressing the gene for BBOX1 caused TNBC cell lines to wildly proliferate. Further investigation showed that it wasn’t carnitinethe enzyme’s end productthat caused this effect. The enzyme itself appeared to be key for TNBC cells’ survival and growth.
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What Is The Prognosis For Triple
A good treatment result depends on several factors. Chemotherapy is what can really make a difference in the outcome. The size of the invasive part of the tumor, and the number of involved lymph nodes can also greatly influence your prognosis, Sun says, but adds that if the cancer has spread , the prognosis is less certain.
There is hope, even with this serious diagnosis, and staying optimistic is essential. It can be stressful and scary to go through chemo, but positive thinking can make a difference. You have to believe that its doing you good, and for most people, it does.
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Early Stage Clinical Trials
In a proof of concept study published in the Lancet, authors investigated olaparib in patients with advanced metastatic breast cancer with germline BRCA1/BRCA2 mutations. They investigated two doses of olaparib at 400 mg BD and 100 mg BD. Approximately half of patients in this study had TNBC with the remainder having other histological subtypes. Patients were heavily pretreated with a median of 3 prior chemotherapy regimens and platinum sensitivity was not needed for trial enrolment. Overall response rates were impressive in this heavily pre-treated population at 41% in the group receiving the higher dose and 22% in the group receiving the lower dose.
Kaufman et al investigated olaparib further in a large phase 2 basket trial with 298 patients in a single-arm study. Patients with any advanced solid-organ malignancy were included if they harboured a gBRCA mutation. In the breast cohort, patients may have received multiple lines of treatment and there was no requirement for platinum sensitivity. Response rates were modest with only 8 of 62 patients responding in this unselected population.
Is Triple Negative Breast Cancer An Aggressive Form Of Cancer
Its true that triple negative breast cancers can grow quickly. But your prognosis or expected outcome depends on more factors than your cancer subtype. Healthcare providers will also consider your tumors size and whether it has spread to your lymph nodes and other parts of your breast. Its also helpful to know researchers are focusing on ways to slow the spread of TNBC.
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Prognosis And Recommended Follow
These complex, multidisciplinary recommendations, including discussions on ALND, postmastectomy RT, and additional adjuvant chemotherapy, reflect how the treatment of TNBC is tailored to both the initial clinical stage and the effects of NAC. NAC serves not only as effective systemic therapy with the prospect of enhancing breast preservation but also as a strategy for identifying patients at greater or lesser risk of recurrence and altering their treatment program based on treatment response. The pathological outcomes at the end of NAC are critical for determining the optimal surgical approach and the need for RT and/or additional systemic treatment. This adaptive decision making, informed by the patient’s experience, and particularly the tumor response, provides powerful justification for neoadjuvant therapy as the preferred approach in stage II and III TNBC .
Neoadjuvant And Adjuvant Settings
A PARP inhibitor appears to have efficacy for neoadjuvant treatment of patients with gBRCAm TNBC. Talazoparib achieved encouraging pCR in patients with gBRCAm breast cancer, including TNBC, and HR+ breast cancer, as a neoadjuvant single-agent without the addition of chemotherapy . Currently a larger, multi-center, neoadjuvant Phase II trial is ongoing. However, the addition of a PARP inhibitor to standard neoadjuvant chemotherapy was found to be not beneficial. In the BrighTNess Phase III trial the addition of PARP inhibitor veliparib to carboplatin and paclitaxel followed by doxorubicin and cyclophosphamide did not improve pCR whereas the addition of veliparib and carboplatin to paclitaxel did. Therefore, the addition of carboplatin but not veliparib to paclitaxel was proposed as a potential component of neoadjuvant chemotherapy for patients with high-risk TNBC .
PARP inhibitors have also been studied as an adjuvant single-agent therapy. The OlympiA Phase III trial was designed to assess olaparib in patients with gBRCAm and high-risk HER2-negative breast cancer who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. The primary outcome measure will be invasive DFS with a time frame of up to 10 years.
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Gut And Breast Microbiome
Historically, breast tumor tissue has been considered a sterile environment, however, recent studies suggest the existence of a local, breast microbiome. Indeed, the composition of breast tissue with abundance of fatty tissue, extensive vasculature, and lymphatic drainage makes it a favorable environment for the growth of bacteria . Comparison of microbial signatures across multiple cancer types revealed cancer type specific microbial signatures that differ between the respective tumors and adjacent normal tissues whereby breast cancer was associated with a particularly rich and diverse microbiome. Furthermore, the breast microbiome has been shown to differ from normal to benign to malignant tissues, as well as between breast cancer subtypes, and in relation to response to immunotherapy .
When Should I Go To The Emergency Room
You might also have unusually strong side effects from your cancer treatment. While your healthcare provider likely gave you medication to help control your side effects, you should go to the emergency room if your side effects continue despite medication.
Many cancer treatments affect your immune system, increasing the chance you will develop infections. Symptoms that might require an emergency room visit during treatment are:
- Fever of 100.5 and above.
- Chills.
- Persistent nausea and vomiting.
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A New Era Of Hope For Patients With Triple
Triple-negative breast cancer is a particularly devastating subtype of breast cancer, as it is often diagnosed in young women and is associated with an exceptionally poor prognosis. The triple-negative designation indicates that the three key features driving most breast cancers are lacking, but it provides no clues as to potential biologic drivers. In the absence of any biologic insights, tailored, targeted treatment decisions have historically not been possible.
Consequently, until as recently as 2018, we have relied exclusively on nonselective cytotoxic agents, with modest success. For example, conventional neoadjuvant chemotherapy confers a pathologic complete response in just 50% to 55% of patients with early-stage triple-negative breast cancer,1-4 and among those who do not achieve a pathologic complete response, approximately one-third will die within 3 years.5 Moreover, patients with metastatic triple-negative breast cancer treated with conventional chemotherapeutics have a median survival of 12 to 18 months and an estimated 5-year overall survival of 11%.6 Thus, therapeutic innovation for early and late triple-negative breast cancer has been desperately needed.
Biologic Insight Leads to Therapies
From biologic insight springs hope for therapeutic innovation. Heather L. McArthur, MD, MPHTweet this quote
Immune Modulation Via Checkpoint Blockade
Antibody-Drug Conjugates
Forecast Finally Changing in Triple-Negative Disease
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