De-escalated Neoadjuvant Dual Anti-HER2 Blockade and Survival Outcomes in Early Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.

Trastuzumab is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. Pertuzumab is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways. Dual HER2 blockade with Trastuzumab and Pertuzumab, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies.

Pathological Complete Response (pCR) after neoadjuvant therapy has strong prognostic significance in HER2+ breast cancer and pCR rates in HER2+/HR− tumors exceed those in HER2+/HR+ tumors, and this in turn correlates with superior Event Free Survival. The FDA approved anti-HER2 dual blockade with Pertuzumab and Trastuzumab, given along with chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer, based on the NeoSphere trial, and for metastatic disease based on positive survival results in the CLEOPATRA trial. The role of chemotherapy free anti-HER2 dual blockade however has remained unclear.

ADAPT (Adjuvant Dynamic marker-Adjusted Personalized Therapy) is one of the first new generation neoadjuvant trials addressing individualization of neoadjuvant therapy in early breast cancer and was initiated to establish early predictive surrogate markers such as Ki-67 for therapy response following a short course of induction treatment, in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment. West German Study Group (WSG)-ADAPT trials were designed separately for HER2+/HR− and HER2+/HR+ breast cancer sub groups as they are biologically distinct, with HER2+/HR− subgroup being more aggressive but also more chemosensitive, as evidenced by response to neoadjuvant therapy and subsequent survival rates.

The WSG-ADAPT HER2+/HR- trial is a multicenter, prospective Phase II/III trial which assessed whether patients with strong early response to dual HER2 blockade alone might achieve pathological Complete Response (pCR), comparable to that of patients receiving dual HER2 blockade and chemotherapy. In this study, 134 patients (N=134) with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer were randomly assigned 5:2 to either receive Trastuzumab and Pertuzumab alone in arm A or with added Paclitaxel in arm B. In Arm A, patients (N = 92) received a loading dose of Trastuzumab 8 mg/kg IV and then 6 mg/kg three weekly along with Pertuzumab 840 mg loading dose and then 420 mg 3 weekly, for a total of 12 weeks. In Arm B (N=42), in addition to Trastuzumab and Pertuzumab as administered in Arm A, Paclitaxel 80 mg/m2 IV was given every week for 12 weeks. Eligible patients had tumors that were ER and PR negative (less than 1%) and HER2-positive (IHC 2+ and FISH positive or IHC 3+ positive). After neoadjuvant treatment, surgery or histological confirmation of non-pCR by core needle biopsy within 3 weeks was mandatory. Pathological Complete Response (pCR) at surgery was defined as no invasive tumor residuals in breast and lymph nodes.

The Primary endpoint was pCR and omission of further chemotherapy was allowed in patients with pCR, and Secondary endpoints included 5 year distant Disease Free Survival (DFS) and Overall Survival (OS). An important objective of this study was to identify an early-responder population with regard to pCR after Trastuzumab and Pertuzumab alone treatment, which is strongly associated with long-term prognosis particularly in HER2+/HR− breast cancer, and assess whether this population might be spared neoadjuvant chemotherapy. Early response was defined as proliferation decrease 30% or more of Ki-67 (compared to baseline) or low cellularity (less than 500 invasive tumor cells) in the 3-week biopsy. The trial was stopped early due to the observed pCR superiority in the dual HER2 blockade plus chemotherapy group. The authors previously reported that the pCR rate in the dual HER2 blockade plus chemotherapy group was 90.5%, compared with 36.3% in the dual HER2 blockade alone. The authors have now reported the first survival data.

After a median follow-up of 5 years, there were no significant differences in DFS, distant DFS and OS between the 2 study groups. The invasive DFS rate was 98% with dual HER2 blockade and chemotherapy and 87% with dual HER2 blockade alone (HR=0.32; P=0.144). Distant DFS was 98% and 92%, respectively (HR=0.34; P=0.313) and Overall Survival was 98% and 94% (HR=0.41; P=0.422). The achievement of a pathologic Complete Response following 12 weeks of treatment was strongly associated with improved invasive DFS at 5 years, irrespective of study group (98.5% versus 82%; HR=0.14; P=0.011). The researchers also examined the benefit of neoadjuvant chemotherapy-free dual HER2 blockade alone and noted that no pCR was observed in patients with low HER2 expression (IHC 1+ or 2+ and FISH positive) and/or basal-like subtype as detected by PAM50 assay. In the total study population, low HER2 expression and/or no early response was strongly associated with worse distant DFS (P=0.029) and invasive DFS (P=0.068).

The authors concluded that excellent pCR and Survival can be accomplished in patients treated by de-escalated 12-week neoadjuvant weekly Paclitaxel and dual HER2 blockade, irrespective of additional chemotherapy use. They added that early pCR after only 12 weeks of neoadjuvant Paclitaxel plus dual HER2 blockade was strongly associated with improved outcome, and may thus serve as a predictive clinical marker for further treatment de-escalation.

De-escalated neoadjuvant pertuzumab+trastuzumab with or without paclitaxel weekly in HR-/HER2+ early breast cancer: ADAPT-HR-/HER2+ biomarker and survival results. Harbeck N, Gluz O, Christgen M, et al. J Clin Oncol 39, 2021 (suppl 15; abstr 503)

Risk of Cardiovascular Diseases among Older Breast Cancer Survivors

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Significant progress in breast cancer screening techniques, as well as new and novel therapies, have resulted in early cancer detection and improvement in the breast cancer 5-year survival rate in the US from 75% in the 1970s to 91% in the 2010s. Cardiovascular Disease (CVD) is the most frequent cause of noncancer-related death, and cardiotoxicities associated with cancer treatments may increase cardiovascular risk in this population of breast cancer survivors. However, few studies have in detail quantified the risks of the different clinically important cardiovascular outcomes. The authors therefore assessed the prevalence of the different clinically specific cardiovascular outcomes at breast cancer diagnosis, and their incidence after diagnosis, among survivors 65 years or older in the US, and compared this with similar women without cancer.

The researchers performed a matched cohort study using prospectively collected data from the SEER-Medicare linked claims-based database and identified all women older than 65 years of age with an incident Stage I-III breast cancer diagnosis in 2004 through 2013. Each patient with breast cancer was matched at diagnosis with 5 cancer-free female counterparts. Baseline prevalence of specific cardiovascular outcomes was measured, and the risk for individual cardiovascular outcomes during follow up was calculated, taking into consideration time since diagnosis, race/ethnicity, prior Cardiovascular Disease (CVD), and age. This study included a total of 91,473 women with breast cancer and 454,197 without breast cancer.

It was noted that women with breast cancer had lower baseline prevalence of all CVDs. Breast cancer survivors had substantially increased risks of Deep Vein Thrombosis and pericarditis, compared with cancer-free female counterparts. There was also evidence of smaller increased risks of sudden cardiac arrest, arrhythmia, heart failure, and valvular heart disease. The increased risks of arrhythmia, heart failure, pericarditis, and Deep Vein Thrombosis were most pronounced in the first year and persisted for more than 5 years after cancer diagnosis. There was evidence of a decreased risk of incident angina, myocardial infarction, revascularization, peripheral vascular disease, and stroke in breast cancer survivors, although this was not constant over time.

The CVD risk during follow up was consistently higher in African American women diagnosed with breast cancer compared with Caucasian women, regardless of whether there was an overall increased or decreased risk of outcomes during the entire follow up period, and this is consistent with racial differences in overall CVD risk in the US.

Finally, there was consistently a greater risk of all cardiovascular outcomes in those diagnosed with Stage III, Grade 3, and ER/PR-negative breast cancer, which may be a reflection of the more aggressive cancer treatment regimens used in these subtypes.

The authors concluded that there is evidence of increased risk of several cardiovascular diseases in elderly women diagnosed with breast cancer in the US, compared with similar women without cancer, with this risk persisting for several years after diagnosis. They added that these results highlight the importance of periodic cardiovascular evaluation throughout the long term follow up of women diagnosed with breast cancer.

Risk of Cardiovascular Diseases Among Older Breast Cancer Survivors in the United States: A Matched Cohort Study. Matthews AA, Hinton SP, Stanway S, et al. J Natl Compr Canc Netw 2021;19:275-284.

Platinum Chemotherapy Inferior to XELODA® in Triple Negative Breast Cancer Following Neoadjuvant Chemotherapy

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Breast cancer is heterogeneous malignancy and using global gene expression analyses, 6 breast cancer intrinsic subtypes have been established. They include Luminal A, Luminal B, HER2-enriched, Claudin-low, Basal-like, and a Normal breast-like group. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is a surrogate for the inherently aggressive Basal-like breast cancer subtype. This group has the worse prognosis compared to other breast cancer subtypes and is usually aggressive, and tumors tend to be high grade. Patients with TNBC are at a higher risk for both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers, with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. Basal-like breast cancer subtype is also a marker of hereditary breast cancer susceptibility. Multiparity may increase the risk of TNBC and reduce the likelihood of developing ER-positive breast cancer. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge.Molecular-Subtypes-of-Breast-Cancer

Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. Patients with TNBC are at a high risk for recurrence if they have residual invasive disease, following completion of standard neoadjuvant chemotherapy.

In the Phase III CREATE-X trial, the addition of adjuvant XELODA® (Capecitabine) therapy was found to be safe and effective in prolonging Disease Free Survival (DFS) and Overall Survival (OS) among patients with HER2-negative breast cancer, who had residual invasive disease on pathological evaluation, following neoadjuvant chemotherapy (N Engl J Med 2017;376:2147-2159).

Based on the preclinical models supporting the use of platinum agents in the TNBC Basal-like subtype, the EA1131 trial was conducted to test the hypothesis that adjuvant platinum chemotherapy would improve invasive DFS compared with XELODA®, in patients with clinical Stage II-III TNBC, who had Basal-like subtype invasive residual disease in the breast, following neoadjuvant chemotherapy. The aim of this study was to assess whether platinum chemotherapy would be as effective, or more effective than XELODA® (noninferiority design with superiority alternative – Hybrid design).

In this study, 410 patients with clinical Stage II or III TNBC who had completed at least one full cycle of taxane with or without anthracycline-containing neoadjuvant chemotherapy were randomly assigned to receive XELODA® 1000 mg/m2 orally twice daily, days 1-14, every 3 weeks, for a total of six cycles, or a platinum agent (treating physician choice of Cisplatin 75 mg/m2 or Carboplatin AUC 6 on day 1) IV, once every 3 weeks, for a total of four cycles. Radiation Therapy before or after study treatment completion, was required for all patients after breast-conservation surgery. Postmastectomy Radiation Therapy was required for patients with primary tumors more than 5 cm or those with 4 or more positive axillary lymph nodes. TNBC subtype (Basal versus non-Basal) was determined by PAM50 in the residual disease. The Primary end point was invasive DFS (time from random assignment to the earliest disease recurrence, invasive contralateral cancer, second primary cancer, or death) in patients with Basal subtype TNBC.

After a recent interim analysis, the Data and Safety Monitoring Committee recommended stopping the trial, as it was unlikely that further follow up would show noninferiority or superiority of platinum chemotherapy. After a median follow up of 20 months, the 3-year invasive DFS among the 308 patients with Basal subtype TNBC for platinum chemotherapy was 42% versus 49% for XELODA®. Further, Grade 3 and 4 toxicities were more common in the platinum chemotherapy group. The 3-year Relapse Free Survival as well as Overall Survival was also in favor of XELODA® group versus Platinum group. There was no benefit noted with platinum chemotherapy in any of the subsets of randomized patients.

It was concluded from this study that platinum agents do not improve outcomes in patients with Basal subtype TNBC, who have residual disease following neoadjuvant chemotherapy, and are associated with more severe toxicities, when compared with XELODA®. All participants in this study had a lower than expected 3-year invasive DFS regardless of study treatment, highlighting the need for better therapies in this high-risk population. The authors added that these study findings have an immediate impact in clinical practice, and adjuvant use of platinum agents in this patient population should only be considered in the context of a clinical trial.

Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131. Mayer IA, Zhao F, Arteaga CL, et al. DOI: 10.1200/JCO.21.00976 Journal of Clinical Oncology. Published online June 06, 2021.

Late Breaking Abstract – ASCO 2021: Adjuvant LYNPARZA® Improves Disease Free Survival in BRCA Positive Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal. Patients with BRCA mutations can present with aggressive, high-risk disease and are at a high risk of recurrence following completion of multimodality therapy including surgery, radiation, and chemotherapy. This is an area of unmet need, warranting identification of additional novel and effective therapies.

BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNAIn a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive.

LYNPARZA® is a PARP inhibitor, that traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. LYNPARZA® is presently approved by the FDA for metastatic HER2-negative breast cancer with BRCA1/2 germline mutation. The researchers in this study evaluated the benefit of LYNPARZA® in patients with germline BRCA-mutated, HER2-negative, early stage breast cancer.MOA-of-LYNPARZA

OlympiA is a multicenter, randomized, placebo-controlled, double-blind, Phase III trial of adjuvant LYNPARZA® after neoadjuvant/adjuvant chemotherapy, in patients with germline BRCA1/2 mutations, and high-risk HER2-negative early breast cancer. This trial enrolled 1836 patients, including triple negative and hormone receptor positive breast cancer. All enrolled patients had already received standard adjuvant or neoadjuvant chemotherapy, surgery and if needed, radiation therapy, for early stage breast cancer (Stage II-III). Inclusion criteria also required that patients have a high risk of disease recurrence and those with lower risk of invasive disease recurrence were excluded. For example, patients with hormone receptor positive breast cancer had 4 or more positive lymph nodes prior to adjuvant chemotherapy. Patients were randomized 1:1 to receive LYNPARZA® 300 mg PO BID continuously for 1 year (N=921) or placebo (N=915). Endocrine therapy and bisphosphonates were allowed. The Primary endpoint was invasive Disease Free Survival (IDFS) and Secondary endpoints included distant DFS (DDFS), Overall Survival (OS) and Safety. The study results were reported early, at a median follow up of 2.5 years, after a planned interim analysis was reviewed by an Independent Data Monitoring Committee.

At the pre-specified interim analysis (2.5 years), the estimated 3-year invasive DFS (IDFS) was 85.9% for patients who received LYNPARZA® compared with 77.1% for those who received placebo (HR=0.58; P<0.001), representing a 42% reduction in the risk of IDFS with LYNPARZA® compared to placebo. The estimated 3-year distant DFS (DDFS) was 87.5% versus 80.4% respectively (HR=0.57; P<0.001). This represented a 43% reduction in DDFS with adjuvant LYNPARZA® compared to placebo. At the time of this interim analysis, Overall Survival data were considered immature. The side effects were consistent with the known safety profile of LYNPARZA®, and no new safety signals were noted during the trial.

The authors concluded that adjuvant LYNPARZA® following adjuvant or neoadjuvant chemotherapy significantly improved invasive DFS and distant DFS with acceptable toxicity, in patients with germline BRCA mutated, and high risk HER-2 negative early stage breast cancer. The authors added that this is the first study to report the benefit of a PARP inhibitor given as adjuvant therapy on survival endpoints, in this patient group. Overall Survival data are awaited, as follow up data matures.

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. Tutt AJ, Garber JE, Kaufman B, et al. June 3, 2021, DOI: 10.1056/NEJMoa2105215.

70-Gene Risk Signature May Determine Long Term Benefit of Endocrine Therapy in Premenopausal Breast Cancer Patients

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Approximately 75% of patients with breast cancer are Hormone Receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.

ZOLADEX® (Goserelin) is a potent synthetic analogue of Luteinizing Hormone-Releasing Hormone (LHRH), also known as a Gonadotropin Releasing Hormone (GnRH) agonist analogue. It stimulates the production of the sex hormones Testosterone and Estrogen in a non-pulsatile (non-physiological) manner, resulting in the disruption of the endogenous hormonal feedback systems, and down-regulation of Testosterone and Estrogen production. Given that premenopausal patients with breast cancer have their disease diagnosed earlier in life, they are at an increased risk of fatal disease during their lifetime. The long term benefit of endocrine therapy, including ovarian suppression, has not been studied in this patient population.

Zipp-trial (STO-5) in one of three well defined randomized, controlled, clinical studies of adjuvant endocrine therapy, conducted between 1990 and 1997 by the Stockholm Breast Cancer Study Group. This trial included premenopausal patients with invasive breast cancer treated with a modified radical mastectomy or breast conserving surgery and axillary lymph node dissection or biopsy. Patients undergoing breast conserving surgery also received adjuvant radiotherapy to the breast (50 Gy over 5 weeks). Patients were included in study irrespective of ER status. All patients with node positive disease electively received adjuvant cytotoxic chemotherapy and those with four or more lymph node metastases received radiotherapy as well.

The Stockholm part of the Zoladex In Premenopausal Patients (ZIPP-trial, STO-5) included 924 patients and the purpose of this analysis was to examine the long-term 20-year benefit of ZOLADEX® and Tamoxifen, stratified by the molecular 70-gene risk prediction signature in this patient population. Patients were stratified by lymph node status and divided into 3 groups: patients with lymph node-negative status, those with 1-3 positive lymph nodes who had received chemotherapy, and those with 4 or more positive lymph nodes who received chemotherapy and locoregional radiotherapy. All of these patients were included in a 2X2 factorial randomization to receive ZOLADEX® 3.6 mg Subcutaneously every 28 days (N=230), Tamoxifen 40 mg orally daily (N=231), ZOLADEX® plus Tamoxifen (N=230), or no endocrine therapy (N = 233), for 2 years. Node-positive patients received adjuvant chemotherapy in addition to endocrine therapy. The median age was 46 years.

The researchers identified clinically relevant breast cancer markers by immunohistochemistry in 729 patients, of whom 610 patients had Hormone Receptor-positive tumors. Molecular risk classification data were available in 465 patients and the 70-gene signature classified patients into groups with either Low risk (N=306) or High risk of disease recurrence (N=159). Of the 610 patients with Hormone Receptor-positive tumors, 160 received ZOLADEX®, 142 received Tamoxifen, 156 received the combination, and 152 received no endocrine therapy (control group).

The researchers noted that the 20-year risk for distant recurrence was significantly reduced in the patients who received ZOLADEX®, Tamoxifen or both, compared with those who did not receive endocrine therapy. The respective Hazard Ratios (HRs) were 0.48, 0.59, and 0.67 after adjusting for prior therapy and tumor characteristics. Stratification by the 70-gene signature demonstrated that Low risk patients derived a significant benefit from Tamoxifen therapy (HR=0.38), whereas ZOLADEX® plus Tamoxifen provided less benefit to these patients ((HR=0.80 and 0.72, respectively). In contrast, patients at High risk had significant benefit from ZOLADEX® therapy (HR=0.22), whereas less benefit was observed with Tamoxifen or ZOLADEX® plus Tamoxifen (HR=0.69 and 0.64, respectively).

The authors concluded that long term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification, with significant benefit from ZOLADEX® noted in High risk patients, whereas Low risk patients benefit from Tamoxifen.

LBA1 – 20-year benefit of endocrine therapy in premenopausal breast cancer patients by the 70-gene risk signature. Johansson A, Dar H, Van ‘T Veer L, et al. DOI:

Role of Chemotherapy in Postmenopausal Women with Node Positive Early Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer were diagnosed in 2020 and about 42,170 women died of the disease. Approximately 25% of patients with Hormone Receptor (HR)-positive, HER2-negative early breast cancer have metastatic lymph node involvement and two third of these patients are postmenopausal. Majority of these patients currently receive chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, HR-positive, HER-negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

In the ground-breaking TAILORx (Trial Assigning Individualized Options for Treatment) study which enrolled 10,273 patients with HR-positive, HER2-negative, axillary node-negative breast cancer, patients were divided into three groups based on their Recurrence Score. Patient with Intermediate Recurrence Score of 11-25 were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. There was no benefit noted from adding chemotherapy to endocrine therapy, for women older than 50 years in this Intermediate RS group, suggesting that a significant percentage of women with node-negative breast cancer do not achieve substantial benefit from chemotherapy. For women 50 years old or younger who received chemotherapy and had a Recurrence Score of 16 to 25, there was a lower rate of distant recurrence and the risk of recurrence and benefit of chemotherapy was further influenced by the tumor size and grade. Whether the results of TAILORx can be extrapolated to women with node-positive breast cancer has remained unclear. It is estimated that approximately 85% of women with node-positive disease have Recurrence Score results of 0-25.

The RxPONDER trial was designed to determine the benefit of chemotherapy, in patients who had a Recurrence Score of 0-25. This trial did not include pre and postmenopausal women with Recurrence Score results 26-100 based on previously published studies suggesting that this patient group benefited from chemotherapy. SWOG S1007 (RxPONDER) is an multicenter, international, prospective, randomized, Phase III trial, in which patients with HR-positive, HER2-negative breast cancer with 1-3 positive axillary lymph nodes were included, to determine which patients would benefit from chemotherapy and which patients could safely avoid it. In this study, a total of 5083 HR-positive, HER2-negative breast cancer patients with 1-3 positive lymph nodes and Oncotype DX Recurrence Score of less than 25 were randomly assigned 1:1 to receive chemotherapy plus endocrine therapy or endocrine therapy alone. Approximately two-thirds of patients were postmenopausal and one-third were premenopausal and had no contraindications to taxane and/or anthracycline based chemotherapy. Patients were stratified by Recurrence Score (0-13 versus 14-25), menopausal status, and axillary nodal dissection versus sentinel node biopsy. The Primary endpoint was Invasive Disease Free Survival (IDFS), defined as local, regional, or distant recurrence, any second invasive cancer, or death from any cause, and whether the effect depended on the Recurrence Score. Secondary endpoints included Overall Survival (OS).

At a median follow up of 5.1 years, there was no association noted between Recurrence Score (RS) values and chemotherapy benefit for the entire study population (P=0.30). However, a prespecified analysis did show a significant association between chemotherapy benefit and menopausal status. Premenopausal women (N=1665) with an RS between 0 and 25 had an IDFS benefit with the addition of chemotherapy to endocrine therapy compared with endocrine therapy alone (94.2% versus 89%, HR=0.54; P=0.0004). This absolute 5.2% benefit in the premenopausal subset was highly significant. The relative risk reduction with the addition of chemotherapy to endocrine therapy for the two RS risk groups 0-13 and 14-25 was consistent in the premenopausal population, with an overall Hazard Ratio of 0.54. The absolute benefit was numerically higher in those with RS 14-25. Consistent benefit was again noted regardless of number of involved lymph nodes, although there was slight variation in the absolute benefit. Postmenopausal women (N=3350) did not benefit with the addition of chemotherapy to endocrine therapy when compared endocrine therapy alone, regardless of Recurrence Score (91.9% versus 91.6%, HR=0.97; P=0.82). Chemotherapy also improved Overall Survival in the premenopausal cohort, although the follow up is limited.

It was concluded from this practice-changing outcomes that postmenopausal women with HR-positive, HER2-negative breast cancer with 1-3 positive nodes and Oncotype DX Recurrence Score of 25 or less can safely avoid receiving adjuvant chemotherapy, whereas premenopausal patients with 1-3 positive nodes and a Recurrence Score of 25 or less should consider adjuvant chemotherapy. The authors added that these finding demonstrate that the great majority of postmenopausal women can be spared unnecessary chemotherapy and receive only endocrine therapy.

First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy ± chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence scores ≤ 25: SWOG S1007 (RxPONDER). Kalinsky K, Barlow WE, Meric-Bernstam F, et al. 2020 San Antonio Breast Cancer Symposium. Presented December 10, 2020. Abstract GS3-00.

FDA Grants Regular Approval to TRODELVY® for Advanced Triple Negative Breast Cancer

SUMMARY: The FDA on April 7, 2021, granted regular approval to TRODELVY® (Sacituzumab govitecan) for patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (mTNBC), who have received two or more prior systemic therapies, at least one of them for metastatic disease. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival of only 2-3 months.

TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

The FDA granted accelerated approval to TRODELVY® in April 2020 based on Objective Response Rate of 33.3% and Duration of Response of 7.7 months in a Phase I/II study. The ASCENT trial served as a confirmatory analysis, expanding the previous TRODELVY® indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

The ASCENT study is an open-label, multicenter, active-controlled, randomized, confirmatory Phase III trial in which 529 patients with unresectable locally advanced or metastatic TNBC patients were enrolled. Eligible patients had relapsed/refractory disease and had received two or more prior systemic therapies (including a taxane), one of which could be in the neoadjuvant or adjuvant setting, if disease progression occurred within 12 months. Patients were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on days 1 and 8 of a 21-day cycle (N=267) or physician’s choice of single-agent chemotherapy (N= 262). The Primary endpoint was Progression Free Survival (PFS) in patients without brain metastases at baseline (N=468), as measured by a blinded Independent Centralized Review. Secondary endpoints included PFS for the total population (with and without brain metastases), Overall Survival (OS), Objective Response Rates (ORR) and Safety.

Among all randomly assigned patients (with and without brain metastases), the median PFS for patients receiving TRODELVY® was 4.8 months, compared with 1.7 months in those receiving chemotherapy (HR=0.43; P <0.0001). This represented a statistically significant and clinically meaningful 57% reduction in the risk of disease progression or death. The median OS was 11.8 months and 6.9 months respectively, in favor of TRODELVY® (HR= 0.51; P<0.0001), representing a 49% reduction in the risk of death. The most common adverse reactions in patients receiving TRODELVY® were fatigue, rash, decreased appetite, nausea, vomiting diarrhea, constipation, alopecia, anemia and abdominal pain.

It was concluded that ASCENT is the first Phase III study of an Antibody Drug Conjugate, with significant PFS and OS improvement over Standard-of-Care chemotherapy, in pretreated patients with metastatic Triple Negative Breast Cancer, fulfilling an unmet medical need.

ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Bardia A, Tolaney SM, Loirat D, et al. ESMO Virtual Congress 2020. Abstract LBA17. Presented September 19, 2020.

Advances in Triple Negative Breast Cancer

Written by: Debra Patt, MD, PhD, MBA
Content Sponsored by: Bristol Myers Squibb
Dr. Patt is a paid consultant for BMS and was compensated for her contribution in drafting this article.

Metastatic triple negative breast cancer (TNBC) is a devastating disease, making up 15% of all cancers, and having a limited outcome with an overall survival average of around a year.1,2 It is a diagnosis of exclusion, as tumor cells do not express the targetable hormone receptors (estrogen or progesterone receptors) or HER2, thus treatment options have historically relied on systemic chemotherapy rather than targeted treatment.3 This aggressive subtype is often associated with an earlier age of onset and an aggressive clinical course. Ethnic disparities have been identified for triple negative disease, with the incidence highest among patients who have a non-Hispanic black ethnic background compared to other ethnic groups.1 Furthermore, African American women are more likely to develop metastases compared to women of other races. Metastatic progression for triple-negative disease is generally characterized by early relapse and predominantly visceral (including liver, pulmonary and central nervous system) metastases.3

Historically, advances in the treatment of triple negative breast cancer have been rare. Multiple immunotherapy options in combination with chemotherapy are now approved in metastatic TNBC for patients with PD-L1 positive, first-line disease, and today there is much excitement about further evidence supporting its use in the metastatic and early stage settings.4 However, no head-to-head data exists to identify the optimal chemotherapy partner for checkpoint inhibition and not all chemotherapy agents appear to provide similar efficacy based on current data, hence more investigations are needed.5,6 Furthermore, while the incidence of immune-related adverse events such as endocrinopathies are low, the permanence of these side effects, particularly in the early stage setting, is concerning to some and should be closely monitored.

Germline BRCA mutations occur in approximately 10–30% of TNBC cases.7 In previously treated metastatic disease, the use of poly (ADP-ribose) polymerase (PARP) inhibitors in germline BRCA mutation positive patients has also shown improvements in survival, with the main reported side effects being hematologic, fatigue and diarrhea.3,8 In heavily pretreated metastatic TNBC patients, the use of antibody-drug conjugates has also resulted in anti-cancer effects.9

While advances in the aggressive and difficult-to-treat triple negative breast cancer subset are promising, all of these recent advances leave us with new treatment options but also unanswered questions. Our knowledge is limited and certainly will improve over time as we understand better predictors of outcome like PD-L1 expression, tumor infiltrating lymphocytes, and other factors as well as the importance of chemotherapy backbone choice. Other agents are now available for previously treated metastatic TNBC patients and further studies will be needed to assess the efficacy of these agents in earlier lines of therapy. Additionally, long-term follow up of studies will also be important to truly understand the impact of these new targeted approaches and the impact of drug tolerability on efficacy and patient quality of life.

1. DeSantis CE, Fedewa SA, Sauer AG, Kramer JL, Smith RA, Jemal A. CA Cancer J Clin. 2016;66:31-42.
2. Marra A, Viale G, Curigliano G. BMC Medicine. 2019;17:90-99.
3. Bergin ART, and Loi S. F1000Research. 2019;8: F1000 Faculty Rev-1342. Published online 2019 Aug 2.
4. Simmons CE, Brezden-Masley C, McCarthy J, McLeod D, Joy AA. Ther Adv Med Oncol. 2020;12:1-15.
5. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, et al. DOI: 10.1200/JCO.2020.38.15_suppl.1000 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1000-1000.
6. Miles D, Gligorov J, Andre F, Cameron D, Schneeweiss A, et al. Annals of Oncology. 2020;31 (suppl 4):S1142-S1215. 10.1016/annonc/annonc325.
7. Vagia E, Mahalingam D, Cristofanilli M. Cancers (Basel). 2020 Apr;12:916-941.
8. Madariaga A, Bowering V, Ahrari S, Oza AM, and Lheureux S. Int J Gynecol Cancer. 2020; 30:903-915.
9. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, et al. N Engl J Med. 2019;380:741-751.

Sugar-Sweetened Beverages May Increase Breast Cancer Mortality

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. It is estimated that more than 3.5 million breast cancer survivors are alive in the US. Understanding risk factors and modifying lifestyle behaviors can impact outcomes in this patient group.

Consumption of sugar-sweetened beverages has significantly increased over the past 3 decades worldwide, increasing the risk of obesity, hypertension and Type 2 diabetes, and in turn impacting cardiometabolic health. It is estimated that among all worldwide yearly deaths from diabetes and cardiovascular diseases, over 178,000 were attributable to sugar-sweetened beverages consumption.

More recently published large prospective French study (BMJ 2019;366:l2408) concluded that consumption of sugary drinks was positively associated with the risk of overall cancer and breast cancer. It has been hypothesized that sugar-sweetened beverages contain large quantities of sucrose and fructose which promote visceral adiposity, which can boost tumorigenesis through alterations in adipokine secretion and cell signaling pathways, independent of body weight. Further, long term consumption of sugary drinks result in high glycemic index or glycemic load, with chronically high blood glucose, and therefore chronically elevated insulin concentration. Insulin increases bioactive IGF-1, as well as proinflammatory markers, such as C reactive protein, and systemic inflammation is thought to promote cancer development by inhibiting apoptosis and stimulating cell proliferation, thereby increasing the risk of several cancers, including breast, liver, pancreas, endometrium, colorectal and bladder. Even though there is growing evidence of an association between sugar-sweetened beverages and increased risk of mortality in various populations, the effect of sugary drinks on mortality among breast cancer patients is unknown.

The researchers in this Western New York Exposures and Breast Cancer (WEB) Study assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among 927 women between ages 35 to 79, who had been diagnosed with breast cancer. In this study, a food frequency questionnaire was used to assess frequency of sugar-sweetened soda consumption in the 12 to 24 months prior to diagnosis of breast cancer. Breast cancer cases were followed for a median of 18.7 years, with ascertainment of vital status via the National Death Index (NDI). This study focused on sugar-sweetened soda, as they are sugar loaded and add extra calories to the diet with no nutritional benefit.

Consumption of sugar-sweetened soda five times or more per week was noted to result in a 62% higher likelihood of dying from any cause and 85% more likely to die from breast cancer specifically, compared to women who never or rarely consumed sugar-sweetened soda. The risk of mortality was similarly increased among ER-positive, but not ER-negative patients, among women with BMI above the median, but not below the median. The risk of total mortality was higher in premenopausal women but not post-menopausal women.

It was concluded from this study that a higher frequency of sugar-sweetened soda consumption was associated with increased risk of total and breast cancer mortality among breast cancer patients, supporting existing guidelines on reducing consumption of sugar-sweetened beverages, including for women with a diagnosis of breast cancer. The authors added that this study provides evidence that diet may impact longevity of women after breast cancer.

Study Finds Regularly Drinking Sugar-Sweetened Soda May Increase Total and Breast Cancer Mortality. Koyratty N, McCann SE, Millen AE, et al. Cancer Epidemiol Biomarkers Prev March 2 2021 DOI: