Triple negative breast cancer (TNBC)

MicroArray techniques divide breast cancer in to subtypes: luminal A, luminal B, HER2 positive, and basal-like subtype.

TNBC subtype of breast cancer lacks expression of the estrogen and progesterone receptors and HER2 amplification.

TNBC accounts for a disproportionate amount of poor outcomes among patients with breast cancer, constituting 10-15% of breast cancers, accounting for greater than 35% of breast cancer related deaths.

Has the worst prognosis among the major subtypes of breast cancer.

TNBC’s tend to present with higher stage and spread more frequently to visceral sites, including the lungs and brain, and less frequently to bone.

Patients often present with stage II or III disease and receive neoadjuvant therapy, historically comprising anthracyclines and taxane based chemotherapy which can produce pathologic complete response rates of approximately 40%.

For patients who achieve pathological complete remission prognosis is excellent, with recurrence rates typically less than 10%.

In patients who  not receive pathological complete response, recurrence rate can approach 50%.

10 year survival rate of less than 50%.

Survival for patients with TNBC after metastatic diagnosis ranges from 17-25 months.

Five-year survival is approximately 25%, and the median survival of 24 months in women with metastatic disease.

Most metastatic recurrences of TNBC occur within five years of diagnosis.

Basal-like subtype is one of the most clinically aggressive subtypes, and commonly is negative for estrogen receptors, progesterone receptors and HER2 gene-triple negative phenotype.

Heterogeneous group of tumors subdivided into apocrine, adenoid cystic, metaplastic, and medullary histopathologic subtypes.

TNBC tend to cluster with the basal or claudin-low tumors.

The main molecular subtype is basal-like (49%), and the second most common type is the claudin-low subtype (30%).

The basal-like type is high in proliferation genes and is genomically unstable.

The claudin-low subtype is relatively low proliferation genes, and is medically more stable.

Triple negative breast cancer molecular assays also show HER2 enriched (9%), luminal A (5%), luminal B (6%), and normal-like (1%) subtypes.

Frequently displays homologous recombination deficiency and a high genomic instability, that may predict sensitivity to DNA-damaging agents, such as platinum and DNA repair inhibitors, including poly polymerase-1 inhibitors

Tumor, mutational burden (TNB) and tumor infiltrating lymphocytes (TILs), are associated with better response to antineoplastic therapy.

In triple negative breast cancer, higher levels of TIL are associated with improved survival even without adjuvant or neoadjuvant therapy.

HER2 at negativity is defined as fluorescence in situ hybridization (FISH) ratio of less than two or 8% positivity below 10% by immunohistochemistry.

Triple negative disease and basal like disease are not identical, and approximately 20 to 30% discordance exists between the two types of lesions: triple negative implies immunohistochemical findings ER, PR and HER2 negative expression, while basal-like subtype is defined by gene expression microarray analysis.

Despite greater initial sensitivity to cytotoxic chemotherapy patients with TNBCs have higher rates of distant metastases and a poorer prognosis compared with patients with hormone receptor positive and/or HER2 positive disease

Compared with ER/PR positive and or HER2 positive counterparts, TNBCs are in general larger, of higher grade, and more likely to be a node positive

TNC are highly mutanegenized and most likely to have demonstrable immune T-cell infiltrates.

Tumor infiltrating lymphocytes is a powerful predictor of outcome.

Tumor immune microenvironment plays an important role in prognosis in response to neoadjuvant chemotherapy in triple negative breast cancer.

Stromal and intratumoral lymphocytes are reproducible markers confirming prognosis value in TNBC.

In triple negative breast cancer tumor infiltrating lymphocytes is associated with a favorable prognosis.

TNBCs are more likely than other types of breast cancers to be infiltrated with immune cells, in particular T cells.

TNBCs are more likely to be positive for a programed death ligand 1 (PD-L 1).

TNBCs has a greater number of non-synonymous mutations, which give rise to tumor specific neoantigens they can activate neoantigen specific T cells to mount antitumor immune response, which can be strengthened by immune checkpoint inhibitors.

Approximately 1,000,000 cases of breast cancer diagnosed worldwide in 2008 and an estimated 172,695 cases will be triple negative (Swain SM).

TNBC accounts for 15-20% of breast cancers.

Overrepresented in pre-menopausal and African women.

Median survival of only 12 months, is associated with visceral metastases and recurrence within 3 years.

Distant metastases tend to recur within the first 3-5 years after diagnosis.

Late recurrences are relatively rare, unlike ER positive cancers, in which up to 50% of distant recurrences develop after 5 years.

Typically high grade, has ductal histology, and high proliferation rate.

TNBC (triple negative breast cancer) associated with higher number of TP53 mutations, higher mitotic index, more marked nuclear pleomorphism, and higher tumor grade compared with endocrine sensitive luminal A tumors (Carey LA).

These TNBCs are more commonly p-cadherin/p63 negative and cytokeratin 5 positive.

Most TNBC cases are invasive ductal carcinoma, a minority represent rare histologic subtypes such as medullary carcinoma, metaplastic carcinoma, and adenoid cystic carcinoma.

Patients who receive a pathological complete response after neoadjuvant chemotherapy have excellent survival, while those who have residual disease are at high risk for recurrence.

Patients attaining a pathologic complete response with neoadjuvant therapy in triple negative breast cancer is associated with a 92% five-year event free survival and an 87% 10 year event free survival.

Patients with triple negative breast cancer are more likely to respond to neoadjuvant chemo therapy.

30 to 50% of patients achieve pathologic complete response with neoadjuvant chemo therapy.

Chemotherapy insensitive triple negative breast cancer is associated with a poor prognosis compared with other breast cancer subtypes for which targeted therapy either enhances chemotherapy effect or treats chemo insensitive disease.

Trials demonstrate that patients who have received neoadjuvant chemotherapy who received a pathological complete response have a greater than 90% rate of distant recurrent free survival.

Associated with obesity.

Multiple pregnancies and early pregnancies, as well as lack of breast feeding are reproductive risk factors.

These lesions are often sensitive to chemotherapy, with basal-like cancers having a complete response rate of 25-40% compared to luminal breast cancers of 7% in studies using anthracycline or anthracycline/taxane based chemotherapy regimens.

Have an underexpression of estrogen receptors, progesterone receptors, HER2, Bcl-2 and Cyclin D1.

Have an overexpression EGFR, c-Kit, Cytokeratins 5, 14, 17, alpha/betal crystallin, p16, p53, and Cyclin E.

Frequently associated with PIK3CA mutations.

Basal-like subtype 1 is associated with DNA and cell cycle damage.

Basal-like subtype 2 has myoepithelial markers and growth factor set signal amplification.

Basal-like subtype is associated with shorter survival, which helps explain the poor prognosis of breast cancer in young African-American women.

Fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.

Patients receiving neoadjuvant chemotherapy confirm tumors with either a basal phenotype or triple negative have a significantly higher pCR rate than luminal A or luminal b type tumors, but residual tumor burden was greater in the basal type or triple negative tumors, correlating with disease free survival (Esserman LJ).

TNBC encompasses claudin-low tumors, enriched with cells that have properties similar to those of stem cells and had features of epithelial to mesenchymal transition and of this interferon rich subgroup has a better prognosis than that usually associated with other triple negative breast cancers.

18-40% of basal-like cancers do not have triple negative phenotype on immunohistochemical analysis.

EGFR are expressed in a large portion of basal-like hormone negative breast cancer.

Fibroblast growth factor receptor (FGFR) Amplification expressed in triple negative breast cancers in up to 9% of cases.

Up to 20% of basal-like cancers express estrogen receptor or over express HER2.

Genetically triple negative breast cancers basal-like cancers are heterogeneous.

Women with basal-like breast cancer, as compared to women without cancer, reach menarche at an earlier age, have a higher body mass index during their pre-menopausal years, have a higher parity, and have a lower lifetime duration of breast-feeding.

In contrast with the risk of the more common low-grade ER positive, luminal A, breast cancer, the risk of basial-like breast cancer rises with increasing parity and increasing ratio of waist to hip circumference (Millikan RC et al).

Both triple negative and basal-like breast cancers occur more frequently in young black and Hispanic women than in young women of other racial or ethnic groups.

B RCA1 or a B RCA2 mutations are noted in 10 to 20% of patients with triple negative breast cancer.

Triple Negative breast cancer is enriched for homologous, recombination DNA repair deficiency.

BRCA1 gene located on chromosome 17 is associated with TNBC’s.

More than 75% TNBC and basal-like breast cancers have BRCA1 mutations.

Approximately 80% of breast cancers that develop in germline BRCA1 mutations carriers are triple negative cancers, and about 50% of breast cancers in BRCA2 mutation carriers are TNBC’s.

Trop-2 is an antigen expressed in the majority of breast cancers, including triple negative breast cancer.

Associated with poor outcomes.

Evidence suggests that germline BRCA breast cancers have above average platinum sensitivity and increased sensitivity to poly polymerase inhibitors (PARP.).

A greater incidence of TNBC’s among interval cases versus screened detected breast cancers.

In advanced triple negative breast cancer brain metastasis manifest in as many as 50% of patients.

Strongly associated with the BRCA1 gene.

BRCA1 and BRCA2 mutations are frequent in TNBC affecting up to 30% of such cases, more frequent than in other breast cancer subtypes.

BRCA mutation screening is recommended for patients with TNBC developing before or at age 60 years of age.

About one in every five patients with TNBC are carriers of mutations of BRCA1 or BRCA2.

Patients with BRCA1/2 with TNBC tend to be younger and have a signiicantly better prognosis.

Patients with BRCA1/2 mutations and TNBC have 5 year recurrence free survival estimate of 86% compared to 51.7% with patients who have wild-type cancers that are TNBC lesions.

BRCA1 gene an important tumor suppressor gene responsible for DNA damage sensing and DNA repair mechanisms.

BRCA1 gene results in deficiencies in proteins encoded for DNA damage repairand genetic instability.

Most BRCA1 gene expression analyses indicate that most BRCA1 associated brest cancers have a basal-like phenotype and are likely to be triple negative (Sorlie T, Irvin WJ).

More than 75% of the BRCA1 mutation patients have a triple negative phenotype, a basal-like phenotype or both.

Because about 15% of TNBC are not basal-like, a smaller proportion of TNBC tumors compared to basal-like cancers are BRCA1 positive (Nofech-Mozes S).

BRCA-1, TNBC and basal-like tumors tend to express basal markers including EGFR, cytokeratins 5,14 and 17 (Irvin WJ).

Compared with luminal tumors TNBC more likely to arise among younger women, women with early menarche, higher parity, younger age at full term pregnancy, shorter duration of breast feeding, use of medications that suppress lactation, higher BMI, and waist-hip ratio and metabolic syndrome (Millikan RC, Dolle JM, Maiti B Vona-Davis L).

Core basal phenotype has triple negative status but also expresses cytokeratin 5, the epidermal growth factor receptor, or both and may have a worse prognosis for breast cancers that are negative for all five markers.

In the Breast Internation Group (BIG) trial triple negative BC, an increased lymphocytic infiltrate was associated with a reduced relapse rate and improved survival, independent type of chemotherapy, and was not observed in hormone receptor positive tumors.

Triple-negative breast cancers tended to be located closer to the chest wall compared to estrogen receptor positive breast cancers.

Higher levels of expression of immune checkpoint molecules compared with ER positive tumors.

Mammogram typically indicates hyperdense mass with calcifications and margins which are  indistinct or circumscribed.

Approximately 18% of cases are not clearly demonstrated on mammogram.

Ultrasound sensitivity is high at 92-100%.

MRI has a high sensitive detecting such lesions demonstrating rim enhancement, smooth margins, lobular shape, enhancement, and elevated T2 signaling.

Most cases are not detected with imaging studies but are palpable masses leading to diagnosis.

Increased risk of TNBC in premenopausal women and in African-Americam women.

Metaplastic TNBC breast cancers tend to express EGFR and are associated with poor prognosis.

Survival duration for patients with metastatic TNBC is shorter, a median of 12-18 months, less than that of patients with ER positive cancers with a median survival of 50-60 months.

Majority of patients with early-stage TNBC will never experience a distant metastatic recurrence or die from their disease.

Medullary TNBC cancers in the basal-like subgroup have high mitotic rates, diffuse lymphoid infiltrates and a better prognosis despite higher grade.

Breast conserving, simple mastectomy or modified radical mastectomy are the initial treatments for TNBC as for other types of breast cancer.

These cancers have a higher chemotherapy sensitivity and higher rates of pathological complete remission after pre-operative chemotherapy.

Approximately 70% of TNBCs contain 20% or more tumor infiltrating lymphocytes in tumor stroma, and the more TIL’s present in the stroma the better the prognosis.

Androgen receptor positive TNBC’s account for aproximally 10% of cases and tend to have a more benign course.

The use of postoperative irradiation is controversial, lacking controlled randomized studies, but follows general recommendations for breast cancer.

Platinum therapies lead to double-strand breaks and cross linking of double-stranded DNA, suggesting in cases of BRCA1 mutations TNBC may be more sensitive to platinum based drugs.

21% of patients with TNBC treated with neoadjuvant platinum demonstrated complete response with 50% showing a good response (Yadav BS et al).

Combination therapy with a anthracycline and cyclophosphamide followed by a taxane is considered standard of care for patients with stage I-III TNBC.

In patients with TNBC treated in neoadjuvant fashion with cis-platinum, paclitaxel, and epirubicin 65% had a pathologic complete remission (Wahba HA et al).

A combination of carboplatinum/taxane may be equally efficacious to anthracycline  neoadjuvant therapy regimens.

Taxanes are beneficial for TNBC cancers based on clinical studies.

In a phase 2 study comparing the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP inhibitory activity, in patients with metastatic TNBC: the addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34%-56%, and the overall response from 32%-52%, and also prolonged the median progression free survival from 3.6 months to 5.9 months and the median overall survival from 7.7 months to 12.3 months (O’Shaughnessy J et al).

Studies suggest TNBC in the metastatic setting are relatively taxane resistant.

Taxanes appear more beneficial in combination with anthracyclines in TNBC.

Anthracyclines in TNBC have mixed results.

Platinum analogues are atypical alkylating agents.although they do not have the structure of classic alkylating agents, they act by binding to DNA, thereby interfering with both replication and transcription.

Platinum analogues have enhanced cytotoxic sensitivity in individuals who carry a BRCA mutation.

In a small percentage of patients with TNBC, a pathologic complete response (pCR) can be achieved with neoadjuvant single-agent cisplatin.

The only setting in which the use of a platinum agent in early-stage breast cancer has been accepted as the stan dard of care is human epidermal growth factor 2 (HER2) positive breast cancer.

Many oncologists use combinations such as docetaxel and carboplatin plus trastuzumab, and now pertuzumab as neoadjuvant or adjuvant therapy in patients with early-stage HER2-positive breast cancer.

The addition of carboplatin to the standard regimen increased the pCR rate in the breast and axillary lymph nodes from 41% to 54%, a highly statistically significant result.

Patients who achieved a pCR or had minimal residual disease at surgery had event-free survival and overall survival rates far superior to those of patients who had more extensive residual disease.

The presence of tumor-infiltrating lymphocytes and markers associated with more aggressive tumor biology are predictive of higher pCR rates overall.

In the CALGB 40603 study the addition of carboplatin increased the pCR rate in the breast and lymph nodes from 43% to 57%, a difference that was statistically significant, and the addition of carboplatin significantly improved disease-free survival at 3 years from 76.1% to 85.8%.

Patients who had a germline BRCA mutation have a higher pCR rate with their control chemotherapy regimen (50% for mutated BRCA vs 33% for wild-type BRCA).

Despite the higher pCR rate with the control regimen in BRCA-mutated patients, the addition of carboplatin raised it further to 62%.

Achievement of a pCR is associated with marked improvement in disease-free survival in both BRCA-mutated and BRCA wild type patients.

Patients with stage I and even early stage IIA (T<3 cm N0) TNBC tend to have a very good prognosis with standard chemotherapy with a taxane and an anthracycline, a finding suggesting that they are unlikely to gain significant benefit from the addition of other agents, including carboplatin.

In patients who have larger tumors or axillary node involvement, those with larger stage IIA, stage IIB, or stage III disease, the patients for whom we are most likely to recommend neoadjuvant chemotherapy, to make them better candidates for breast conservation or to limit the extent of their axillary nodal sampling by pCR or minimal residual disease is more likely to be achieved with the addition of carboplatin to the standard chemotherapy regimen.

Improved Prediction in Triple Negative and HER2 Positive Breast Cancer

Data from 2188 patients with pCRs from five neoadjuvant trials (GeparTrio, GeparQuattro, GeparQuinto, GeparSixto and GeparSepto) were analyzed for the primary endpoint of disease-free survival (DFS) and the secondary endpoints of distant DFS (DDFS) and overall survival (OS).

DFS was significantly associated with nodal status, with a 70 per cent increased risk for patients with any number of involved nodes as compared with those who had node-negative disease.

A significantly worse DFS was seen for lobular tumor type compared with non-lobular tumors.

Larger tumors also brought increased risk of recurrence.

There was an increased DFS risk of 61 per cent in patients who had T3 or T4 tumors compared with those with T1 status.

OS was significantly worse in patients with T3 and T4 tumors compared to those with T1 tumors.

Patients with lobular tumor type were?2.85 times more likely to die than those with other types.

Nodal involvement also resulted in a trend for worse OS.

The study concluded that initial tumor size and nodal status and histological tumor type remained prognostic factors for long-term outcome even when pCR had been achieved.

Neoadjuvant chemotherapy is the standard of care in patients with triple negative disease and HER2 positive disease. mainly in those with stage two or greater tumors, and was the preferred treatment because it had the advantage of giving an early indication of chemotherapy efficacy.

Traditional clinical factors are more prominent than biologic ones for predicting relapse.

Preoperative chemotherapy is optimal for all patients with triple negative and HER2 positive disease irrespective of their risk group.

A number of studies have looked at carboplatin/taxane regimens without an anthracycline in early stage TNBC, and have demonstrated pCR rates in the 50% to 65% range, and patients in these studies were spared the short- and long-term toxicities of an anthracycline.

Patients with triple negative breast cancer havr higher levels of PD-L1 expression than  another breast tumor types.

Pembrolizumab, a humanized PD-1 antibody binds with high affinity to its PD-1 receptor and has significant activity in PDL-1-positive triple negative breast cancer.

Among patients with advanced triple negative breast cancer whose tumors expressed PD – L1 at a combined positive score of 10 or more, the addition of Pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone (KEYNOTE 355).

In patients with early triple negative breast cancer, neoadjuvant pembrolizumab, plus chemotherapy, followed by adjuvant Pembrolizumab after surgery, resulted in significantly longer event free survival than neoadjuvant chemotherapy alone (KEYNOTE-522).

The combination of pembrolizumab and eribulen in the ENHANCE/Keynote-150 study demonstrated a 26%response rate in metastatic TNBC.

In patients with early triple negative breast cancer, neoadjuvant Pembrolizumab plus chemotherapy, followed by adjuvant Pembrolizumab after surgery, resulted in significantly longer event free survival than neoadjuvant chemotherapy alone.

Among patients with TNBC, the percentage of patients with pathological complete response is significantly higher among patients who receive  pembrolizumab plus neoadjuvant chemo therapy than among those who receive placebo plus neoadjuvant chemo therapy ( Schmidt P).

The addition of pembrolizumab to polychemotherapy improves outcomes in patients with high risk early stage triple negative breast cancer: this regimen is highly efficacious with higher complete pathological response rates, and clinically meaningful improvements in event free survival.

The combination of Pembrolizumab and chemotherapy is associated with significant high-grade treatment related toxicity.

The 5 year risk of recurrence of small, node-negative TNBC is low and results in a lower treatment benefit.

Present guidelines indicate that there is no adjuvant chemotherapy for TNBC

With 0.5 cm or less tumors but is recommended for lesions 1 cm or greater.

For tumors 0.6 cm-1.0 cm adjuvant chemotherapy can be considered.

Adjuvant therapy for TNBC Is recommended for patients with lymph node positive disease with an anthracycline/taxane based regimen.

Adjuvant radiation therapy in elderly triple negative breast cancer patients treated with lumpectomy is associated with a sixfold decrease in all-cause mortality and breast cancer specific mortality (Szeja S et al).

Antiandrogens may be effective as 80% of TNBC in advanced cancer stage have some level of androgen receptor expression.

Eribulin has demonstrated improved survival in patients who received at least 2 prior chemotherapy treatments.

The phase III ETNA trial found no difference in pathologic complete response (pCR) rates between neoadjuvant paclitaxel and nab-paclitaxel in women with ERBB2/HER2-negative breast cancer.

Sequential anthracycline and taxane therapy are standard as adjuvant therapy for high-risk breast cancer, and the addition of a taxane to an anthracycline has also shown a doubling in the rate of pCR in the neoadjuvant setting.

The risk of disease recurrence after anthracycline/taxane chemotherapy ranges from approximately 10% in patients with stage I disease and up to 25 to 50% in patients  with stage III disease:clinical studies suggest such patients with residual breast  or nodal disease should be offered adjuvant capecitabine.

TNBC patients who have circulating tumor DNA and or circulating tumor cells after definitive treatment are significantly more likely to develop recurrent disease and die of TNBC compared with patients with undetectable ctDNA.

nab-paclitaxel, the nano-particle, albumin-bound paclitaxel allows for infusion of the agent without steroid premedication that is otherwise required with paclitaxel.

A directly compared nab-paclitaxel and paclitaxel in the neoadjuvant setting in 695 patients (346 nab-paclitaxel, 349 paclitaxel) with newly diagnosed ERBB2/HER2-negative breast cancer.

The rate of pCR was improved with nab-paclitaxel, but this did not reach significance. The pCR rate with nab-paclitaxel was 22.5%, compared with 18.6% with paclitaxel.

A high rate of pCR was achieved by those with triple-negative tumors, regardless of whether they received nab-paclitaxel (41.3%) or paclitaxel (37.3%).

The data do not show a different outcome of paclitaxel vs nab-paclitaxel in triple-negative or in hormone receptor positive tumors.

Early phase studies suggest immunotherapy with checkpoint blockade in patients with PD-L1 positive tumors may be beneficial, particularly when combined with multi agent chemotherapy.

Atezolizumab provided durable clinical benefit in patients with metastatic disease.

Approval to the frontline combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1positive triple-negative breast cancer (TNBC).

The approval is based on the phase III IMpassion130 trial, in which the addition of the PD-L1 inhibitor atezolizumab to nab-paclitaxel reduced the risk of progression or death by 40% compared with nab-paclitaxel alone in this patient population.

The addition atrzollizumab to carboplatinum, significantly improved survival of patients with metastatic TNBC  regardless of PD-L1 status.

The first cancer immunotherapy regimen to be approved in breast cancer,

The double-blind IMpassion130 study evaluated the efficacy and safety of the PD-L1 inhibitor plus chemotherapy versus nab-paclitaxel alone in treatment-naive patients with metastatic TNBC.

Patients were randomized 1:1 to receive nab-paclitaxel at 100 mg/m2 intravenously on days 1, 8, and 15 of the 28-day cycle with atezolizumab at 840 mg intravenously (n = 451) on days 1 and 15 of a 28-day cycle or with placebo (n = 451):Treatment was given until disease progression or unacceptable toxicity.

Capecitabine improves both disease-free and overall survival (DFS and OS) when used as an add-on to other standard chemotherapy, either before or after surgery.

The meta-analysis showed that adding capecitabine to standard chemotherapy in TNBC improves DFS by 18% and OS by 22%.

In a randomized clinical trial of patients with early-stage triple negative breast cancer who receives standard adjuvant treatment, low-dose  capecitabine maintenance therapy for one year, compared with observation, resulted in significantly higher five-year disease free survival of 82.8% versus 73% percent for risk of recurrence or death.

Preferred options in the second line setting for TNBC’s oared sacituzumab and trastuzumab-deruxtecan.

PD-L1 expression, which was defined as at least 1% on tumor-infiltrating immune cells to be positive.

Progression free survival (PFS) of 7.4 months with atezolizumab/nab-paclitaxel and 4.8 months with chemotherapy.

Moreover, the 1-year PFS rates were 29% and 16% with atezolizumab/nab-paclitaxel and nab-paclitaxel, respectively.

The median PFS with atezolizumab/nab-paclitaxel and nab-paclitaxel was 7.2 months and 5.5 months respectively.

The1-year PFS rates were 24% in the combination arm and 18% in the nab-paclitaxel arm.

At a 12.9-month follow-up, an interim OS analysis of the PD-L1-positive population showed a clinically meaningful improvement with added atezolizumab at 25.0 months versus nab-paclitaxel alone at 15.5 months.

The addition of immunotherapy to neoadjuvant chemotherapy substantially increases toxicity and still lacks biomarkers to select patients.

Two-year OS rates were 54% and 37% in the immunotherapy/chemotherapy and chemotherapy arms, respectively.

KEYNOTE-522 Neoadjuvant treatment with pembrolizumab and chemotherapy showed a pathological complete response rate that was 13.6% higher compared with chemotherapy alone:The pathological complete remission rate with 63% in the Pembrolizumab  group.

The combination of nirparinb and pembrolizumab has significant antitumor activity in patients with a advanced metastatic TNBC, and higher response rates in those with tumor BRCA mutations.

The proton pump inhibitor (PPI) omeprazole may be a useful addition to treatment for triple-negative breast cancer, as it boosted the expected rate of tumor disappearance among women with early-stage disease, according to the results of a phase 2 trial.


PPIs inhibit fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.


The pathologic complete response (pCR) rate was 71% in the study population, which is higher than the typical 40% seen in patients treated with standard AC-T (adriamycin and cyclophosphamide plus a taxane).

FASN, which is an enzyme, helps generate fatty acids that are a key to cancer cell survival. 

FASN is primarily found in hormone-dominated tissue such as those of the endometrium, prostate, and breast.



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