Tag: Breast Cancer

Novel Ultrasensitive Liquid Biopsy Detects Minimal Residual Disease in Early Stage Breast Cancer

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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 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease largely due to metastatic recurrence. Recurrent disease can occur early, but majority of patients with hormone receptor-positive breast cancer may develop recurrent disease decades, following their initial diagnosis. Once a diagnosis of metastatic breast cancer is established, it is generally incurable.

Systemic recurrence likely arises from micrometastatic disease present at initial diagnosis, which is undetectable by imaging or conventional blood tests. Adjuvant systemic therapy is recommended to eradicate micrometastatic disease and reduce the risk of cancer recurrence. However, current clinical tools are not accurate in identifying which patients would benefit from adjuvant systemic therapy and further are unable to, in real-time, predict whether the recommended therapies have achieved their therapeutic objective. Therefore, more sensitive techniques to detect micrometastatic disease are needed, so that patients receive the most appropriate and optimal therapy, with improved outcomes.

Recently published studies have shown that detection of circulating tumor DNA (ctDNA) in the peripheral blood may identify patients at risk of relapse following definitive therapy using digital droplet Polymerase Chain Reaction (ddPCR) assays. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. The clinical sensitivity of this technique however is limited at the early postoperative time points, at which treatment decisions are usually made, and the lead time prior to clinical manifestation of overt metastatic disease has been relatively short. This is because presently available techniques track one or few mutations and are unable to detect MRD when the fraction of cancerous cell free DNA (cfDNA) in the bloodstream is low.

The authors developed an ultrasensitive blood test for tracking hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD), with a 1,000-fold lower error rate than conventional sequencing, to identify patients who might benefit from additional systemic treatment or de-escalation of therapy. The authors performed Whole-Exome Sequencing (WES) to define several hundred mutations from each patient’s tumor, and to limit potential errors, selected somatic SNVs (Single Nucleotide Variants) to track, using duplex sequencing in cfDNA and employing strict criteria. The detection of 2 or more mutations in a cfDNA sample was considered MRD-positive and any mutations found in a patient’s own genomic DNA was excluded.

For this study, the authors identified 142 patients who had been treated for Stage 0-III breast cancer with curative intent surgery, had postoperative blood and plasma samples available. Overall, 92% of patients received either neoadjuvant, or adjuvant chemotherapy, 76% received adjuvant endocrine therapy and 73% received adjuvant radiation treatment. Approximately 2% of patients had Stage 0 disease, 23% had Stage I, 48% had Stage II, and 27% had Stage III breast cancer at diagnosis. The MRD levels were tracked post-op (median 3.5 months) and 1 year out (median 14.2 months). The patients were monitored for distant recurrences for up to 13 years. A median of 57 mutations were targeted in each patient, identified via Whole-Exome Sequencing of primary tumor tissue and genomic DNA from whole blood. About 78% of patients had post-op samples available, while 86% had 1-year samples. The Primary objective of this study was to determine the predictive power of MRD testing and associated lead time to recurrence, in patients treated for early-stage breast cancer.

The median lead time (the time from a positive test to diagnosis of metastatic disease) between the first MRD-positive result and disease recurrence was 18.9 months in the patients with the most mutations tracked. This is significantly longer than what has been seen in prior studies. Distant disease recurrence was shown to be more likely if MRD was detected at the 1-year mark (HR=20.8; P<0.0001) compared with the post-op setting. Among these patients, the positive and negative predictive values for distant recurrence, was 0.70 and 0.77, respectively. Overall, the clinical sensitivities were 81% in patients with newly diagnosed metastatic breast cancer, 23% in the post-op setting, and 19% at the one year in early stage disease, and highest among patients with the most tumor mutations available to track. The authors noted that their testing methodology was 100-fold more sensitive than ddPCR, when tracking 488 mutations.

It was concluded that the ultrasensitive blood test developed by investigators for Minimal Residual Disease (MRD) could identify survivors who might benefit from additional systemic treatment versus de-escalation. MRD detection was strongly associated with distant recurrence and provided significant lead time to recurrence, enabling early therapeutic intervention in patients who may otherwise develop metastatic recurrence. The authors recommended that future blood-based Whole-Genome Sequencing assays should aim for extra sensitivity, to identify enough mutations to track in all patients.

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer. Parsons HA, Rhoades J, Reed SC, et al. Clin Can Res. DOI: 10.1158/1078-0432.CCR-19-3005. Published June 2020.

Favorable Outcomes with KADCYLA® in HER2+ Breast Cancer Irrespective of Mutational Status

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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 will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response (pCR) rate of 40-60%. Those without a pCR tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy. KATHERINE trial was conducted to address an unmet need, and evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy, in patients with residual invasive cancer at surgery.Mechanism-of-Action - KADCYLA

The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The Primary end point was invasive Disease Free Survival (iDFS-defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group, which translated to an absolute improvement of 11.3%. Invasive Disease Free Survival (iDFS), which was the Primary end point of the study, was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001).This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.

The authors in this publication reported the exploratory analyses of the relationship between iDFS, and biomarkers potentially related to response. The authors focused on pathways that have been implicated in resistance to HER2 treatment such as pathways associated with PIK3CA mutations, as well as HER2 and PD-L1 expression in the post-neoadjuvant residual surgical samples.

In the first part of this biomarker analysis, a total of 1,363 available post-neoadjuvant surgery samples were analyzed through DNA sequencing for PIK3CA mutations. In the second part of this analysis, mRNA expression through RNA sequencing was determined on 1,059 tissue samples of which 244 were pre-neoadjuvant samples and 815 were post-neoadjuvant surgical samples. Because the post-neoadjuvant surgical samples were representative of the entire Intent-To-Treat (ITT) patient population, biomarker analysis for markers such as HER2, PD-L1, CD8, and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitor signatures, were performed by using post-neoadjuvant surgical samples.

The authors noted that in the ITT population (N=743), PIK3CA mutation status had no impact on outcomes when treated with KADCYLA®. Among those patients with mutated tumors who received KADCYLA® and HERCEPTIN®, the iDFS rates were 88.9% versus 77.9%, respectively (HR=0.54) and among those with non-mutated tumors the Invasive Disease Free Survival rates were 88.3% versus 77.0%, respectively (HR=0.48). There was no prognostic impact of PIK3CA mutations in this cohort of patients and the 3 year iDFS rates were almost identical between the mutated and non-mutated tumors.

The authors next looked at HER2 gene expression in the post-neoadjuvant surgical samples and noted that patients who had a tumors with high HER2 expression in the post-neoadjuvant residual surgical samples, and received subsequent treatment with HERCEPTIN®, had the worst outcomes with worse iDFS. This detrimental effect was not seen in the KADCYLA® group, suggesting that residual tumors that have a high HER2 expression in this setting are resistant to HERCEPTIN® but not to KADCYLA®.

When patients were evaluated based on their tumor PD-L1 expression, low PD-L1 expression in post-neoadjuvant residual tumors was associated with a worse outcome for those who received treatment with HERCEPTIN®, whereas treatment with KADCYLA® did not impact outcomes. These findings suggested that PD-L1 may be involved in some resistance mechanisms.

It was concluded that in the KATHERINE trial biomarker analysis, PIK3CA mutation status did not influence outcomes in either treatment groups. However, in the post-neoadjuvant HERCEPTIN® group, high HER2 expression and low PD-L1 expression was associated with less favorable outcomes. The benefit with KADCYLA® in this patient population was independent of all biomarkers assessed.

Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. Denkert C, Lambertini C, Fasching PA, et al. J Clin Oncol. 2020;38(suppl 15):502. doi: 10.1200/JCO.2020.38.15_suppl.502

First Line KEYTRUDA® plus Chemotherapy Significantly Improves PFS in PD-L1-High Triple Negative Breast Cancer

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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 will be diagnosed in 2020 and about 42,170 women will die of the disease. 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 (PFS) of only 2-3 months.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity.

Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10% to 21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first-line treatment of triple-negative metastatic breast cancer.

KEYNOTE-355 is a randomized, double-blind, phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2 IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (yes vs no). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and safety. The median follow up for patients assigned to receive KEYTRUDA® was 17.5 months and 15.5 months for the placebo group. The authors reported the results from an interim analysis conducted by an Independent Data Monitoring Committee (IDMC).

KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82). Formal statistical significance was not tested in the ITT population. Overall Survival data are pending. Adverse Events (AEs) were similar in both treatment groups, although immune-related AEs occurred at a higher incidence in the KEYTRUDA® arm.

It was concluded that KEYTRUDA® in combination with several chemotherapy regimens, showed a statistically significant and clinically meaningful improvement in PFS, compared with chemotherapy alone, in patients with previously untreated locally recurrent, inoperable or metastatic TNBC, whose tumors expressed PD-L1 with a Combined Positive Score (CPS) of 10 or more. This data may be particularly relevant for patients who may have received a taxane in the adjuvant setting within a year, and could be more appropriately treated with a non-taxane regimen, in combination with KEYTRUDA®.

KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortes J, Cescon DW, Rugo HS. et al. J Clin Oncol 38: 2020 (suppl; abstr 1000)

PIQRAY® Effective after Progression on CDK Inhibition in Advanced Breast Cancer

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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 will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease and about half of patients with primary breast cancer will progress later to the metastatic stage. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Most of these patients with advanced disease in the current era are treated with a combination of CDK4/6 inhibitor and endocrine therapy (often an oral Aromatase Inhibitor), based on survival data. However, resistance to these regimens typically develops in a majority of the patients.

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2-negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.Alpelisib-Mechanism-of-Action

PIQRAY® is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to PIQRAY® than those without the mutation, across a broad range of tumor types. In the SOLAR-1 Phase III trial, there was a 35% improvement in Progression Free Survival (PFS) in patients randomized to PIQRAY® plus FASLODEX®, compared to the placebo plus FASLODEX® group, among postmenopausal patients with PIK3CA-mutated, HR+/HER2- negative, advanced breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a CDK 4/6 inhibitor. However in this study, only 6% had received prior CDK4/6 inhibitor therapy and there is presently limited data available, to inform treatment decisions in patients who progress on AI and CDK 4/6 inhibitor combination.

BYLieve is an ongoing, prospective, open-label, Phase II, non-comparative trial, which evaluated the benefit of PIQRAY&reg in combination with endocrine therapy in patients with HR+, HER-negative, PIK3CA-mutated, advanced breast cancer, who progressed on or after a prior therapy including CDK inhibitor. This study included 3 patient cohorts– Cohort A included patients who received a CDK4/6 inhibitor plus an AI as immediate prior therapy, Cohort B included patients who received a CDK4/6 inhibitor plus FASLODEX® (Fulvestrant) as immediate prior therapy, and Cohort C included patients who progressed on/after an AI and received chemotherapy or endocrine therapy as immediate prior treatment.

The authors in this publication shared findings from Cohort A group of patients, who had received CDK4/6 inhibitor plus an AI as their immediate prior therapy. Cohort A enrolled 127 patients of whom 121 patients had centrally confirmed PIK3CA mutation. Patients in Cohort A received PIQRAY® 300 mg orally once daily along with FASLODEX® 500 mg IM on Day 1 and 15 of cycle 1 followed by Day 1 treatment, of each 28 day cycle thereafter. The median patient age was 58 years. Seventy percent (70%) of patients had received one prior metastatic regimen, none of the patients had received FASLODEX® as a first-line metastatic agent, and 60% of patients had secondary endocrine resistance. The median follow up was 11.7 months. The Primary endpoint was proportion of patients alive without disease progression at 6 months. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Overall Survival (OS), and safety.

The Primary endpoint was met and the proportion of patients with confirmed PIK3CA mutation and without disease progression at 6 months was 50.4%. The median PFS was 7.3 months. Among the 121 patients in Cohort A with a confirmed PIK3CA mutation, the response rate, which was all partial responses was 17.4%, and 45.5% achieved stable disease.

Although the BYLieve trial did not have a control group to allow comparing patients in Cohort A to patients receiving other standard therapies, the authors conducted a weighted/matched analysis between the patients in Cohort A of the BYLieve trial and a Real-World similar group of 95 patients with HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, who were treated with standard therapies. The Real-World patient data was obtained from the de-identified clinic-genomic database of Flatiron Health and Foundation Medicine. These 95 patients had received a wide range of regimens, with the most frequent being XELODA® (Capecitabine) monotherapy, FASLODEX® monotherapy, FASLODEX® plus IBRANCE® (Palbociclib), AFINITOR® (Everolimus) plus AROMASIN® (Exemestane), FASLODEX® plus FEMARA® (Letrozole), and IBRANCE® monotherapy.

Unadjusted results showed a median PFS of 7.3 months in BYLieve Cohort A versus 3.6 months in the Real-World cohort. Similar outcomes were noted when data were weighted by odds, propensity score matching, and exact matching.

It was concluded that the BYLieve trial is continuing to show clinically meaningful efficacy with a combination of PIQRAY® and FASLODEX® in HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, post CDK inhibitor treatment, building further on the findings of SOLAR-1 trial. The matched analysis comparing BYLieve with Real-World Data in the post-CDK4/6 inhibitor setting, further supports use of PIQRAY® plus FASLODEX® for this patient group.

Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Rugo HS, Lerebours F, Ciruelos E, et al. J Clin Oncol 38: 2020 (suppl; abstr 1006).

Late Breaking Abstract – ASCO 2020: Local Therapy Does Not Extend Survival in Newly Diagnosed Metastatic Breast Cancer

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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 will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease. Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy. It has been hypothesized based on retrospective analyses, that the addition of surgical resection of the primary tumor in the breast, to systemic therapy, in patients presenting with Stage IV disease, improved survival. Randomized clinical trials however have provided conflicting results.

E2108 is a randomized, Phase III trial which evaluated the benefit of locoregional treatment for the intact primary breast tumor, following initial systemic therapy, in newly diagnosed breast cancer patients presenting with Stage IV disease. In this study, 256 eligible patients with de novo metastatic disease, who did not progress during a 4-8 months period, while on optimal systemic therapy based on patient and tumor characteristics, were randomized to either continue systemic therapy alone (N=131) or combine it with locoregional therapy such as surgery and radiation for the intact primary breast tumor (N = 125). Of the 125 patients who received early locoregional therapy, 109 patients underwent surgery of whom 87 had free margins and 74 patients received locoregional radiation therapy. The Primary endpoint was Overall Survival (OS), and Secondary endpoint was locoregional disease control.

At a median follow up of 59 months, there was no significant difference in Overall Survival (OS) between the optimal systemic therapy plus locoregional therapy compared with optimal systemic therapy alone (3-year OS rate was 68.4% versus 67.9%; HR=1.09; P=0.63). Further, the addition of locoregional therapy to systemic therapy, also failed to improve 3-year Progression Free Survival (P=0.40). There was however significantly higher locoregional recurrence or progression in the systemic therapy alone group compared with the systemic therapy plus locoregional therapy group (3-year rate 25.6% versus 10.2%, P=0.003). Health-related Quality of Life measures such as depression, anxiety and well-being were significantly worse in patients who underwent systemic therapy plus locoregional therapy, compared with systemic therapy alone.

The authors concluded that for patients with a new diagnosis of breast cancer presenting with Stage IV disease, surgery and radiation for the primary breast tumor should not be offered, with the expectation of a survival benefit.

A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: a trial of the ECOG-ACRIN Research Group (E2108). Khan SA, Zhao F, Solin LJ, et al. J Clin Oncol 38: 2020 (suppl; abstr LBA2)

PHESGO®

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The FDA on June 29, 2020 approved a new fixed dose combination of Pertuzumab, Trastuzumab, and Hyaluronidase–zzxf (PHESGO®) for the following indications:

A) Use in combination with chemotherapy as:
1) Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer
2) Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

B) Use in combination with Docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

PHESGO® is a product of Genentech, Inc.

Dietary Supplement Use during Adjuvant Chemotherapy May Increase Risk for Breast Cancer Recurrence

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SUMMARY: The Council for Responsible Nutrition reported that 77% of Americans consume dietary supplements. With the growing awareness regarding health, fitness and nutrition, the market size for dietary supplements is projected to hit a valuation of $349.4 billion by 2026.

Patients often use dietary supplements following a diagnosis of cancer, even though clinical recommendations discourage the use of antioxidant supplements during chemotherapy. One of the mechanisms of action of cytotoxic chemotherapeutic agents is through the generation of Reactive Oxygen Species (ROS). The use of dietary supplements during treatment, particularly antioxidants, could reduce the efficacy of cytotoxic agents. DELCaP study was conducted to address this concern.

DELCaP (Diet, Exercise, Lifestyle and Cancer Prognosis) trial is a prospective observational study, ancillary to an intergroup therapeutic clinical trial for high-risk breast cancer, conducted to evaluate associations between supplement use, particularly antioxidants during chemotherapy treatment, and breast cancer survival outcomes.

The Phase III SWOG S0221 trial evaluated the optimal dose and schedule of Anthracycline/Taxane adjuvant chemotherapy in women with high-risk early breast cancer. The current analysis involved a cohort of 1,134 of 2,014 patients enrolled in this study, who answered a baseline and follow-up questionnaires that included their use of dietary supplement at enrollment and during treatment. The authors then analyzed associations of dietary supplement use with clinical outcomes, after adjusting for clinical and lifestyle factors. Approximately 18% of patients used antioxidants such as Vitamins C, A, and E, Carotenoids or Coenzyme Q10 during treatment, whereas 44% of patients took multivitamins during chemotherapy.

It was noted from this analysis that the use of any antioxidant supplement (Vitamins A, C, and E, Carotenoids and Coenzyme Q10), both before and during adjuvant treatment was associated with an increased risk of recurrence versus no such use of supplements (HR=1.41; P=0.06). There was also a nonsignificant increased risk of overall mortality with the use of any antioxidant supplement (HR=1.40; P=0.14). There was a weaker relationship of outcomes with individual antioxidants and this may perhaps be due to the small numbers of patients. With regards to nonoxidants, Vitamin B12 use both before and during chemotherapy was significantly associated with poorer Disease Free Survival (HR=1.83; P<0.01) and Overall Survival (HR= 2.04; P<0.01). Use of iron during chemotherapy was also significantly associated with recurrence (HR=1.79; P<0.01), as was use both before and during treatment (HR=1.91; P=0.06). Results were similar for Overall Survival. Multivitamin use however was not associated with survival outcomes.

The researchers based on this analysis concluded that the use of antioxidant and nonantioxidant dietary supplements, but not multivitamins, before and during adjuvant chemotherapy may be associated with inferior treatment outcomes, in patients with early stage high risk breast cancer. They added that caution should be exercised by patients, when considering the use of supplements, other than a multivitamin, during chemotherapy, and patients should try to get their vitamins and minerals including antioxidants through food products..

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). Ambrosone CB, Zirpoli GR, Hutson AD, et al. J Clin Oncol. 2019;38:804-814

FDA Approves TRODELVY® for Advanced Triple Negative Breast Cancer

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SUMMARY: The FDA on April 22, 2020, granted accelerated approval to TRODELVY® (Sacituzumab govitecan-hziy), for adult patients with metastatic Triple-Negative Breast Cancer (TNBC), who received at least two prior therapies for metastatic disease. 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 will be diagnosed in 2020 and about 42,170 women will die of the disease.

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.

IMMU-132-01 is a Phase I/II, basket design, open-label, single-group, multicenter trial involving patients with various types of advanced epithelial cancers, who have received at least one previous therapy for metastatic disease. (One example of a basket design is a single drug evaluated in multiple baskets, with each basket representing a different malignancy or tumor site with the same target). A total of 108 patients with metastatic Triple-Negative Breast Cancer (TNBC) were enrolled between June 2013 and February 2017. Patients received TRODELVY® 10 mg/kg IV on days 1 and 8 every 21 days. Tumor imaging was obtained every 8 weeks, and patients were treated until disease progression or intolerance to therapy. The median patient age was 55 years. Enrolled patients had a median of 3 prior anticancer regimens and 98% had received taxanes and 86% had received anthracyclines. The Primary efficacy end point was the Objective Response Rate (ORR). Other efficacy end points included Time to Response and Duration of Response in patients who had a response, the Clinical Benefit Rate (defined as a Complete or Partial Response or stable disease for at least 6 months), Progression Free and Overall Survival. The median duration of follow up for this basket of 108 patients with metastatic TNBC was 9.7 months.

The Objective Response Rate was 33.3% including a Complete Response Rate of 2.8%. The median Time to Response was 2.0 months and the median Duration of Response was 7.7 months. The Clinical Benefit Rate was 45.4%. There was no meaningful difference in response rates in the various patient subgroups including patient age, onset of metastatic disease, number of previous therapies and the presence or absence of visceral metastases. The median PFS was 5.5 months and median OS was 13.0 months. The most common adverse reactions were, possibly severe neutropenia and diarrhea, fatigue, nausea, vomiting, alopecia and abdominal discomfort.

It was concluded that TRODELVY® was associated with durable Objective Responses in patients with heavily pretreated metastatic Triple Negative Breast Cancer. This unique Antibody Drug Conjugate may be of potential benefit for other Trop-2 expressing advanced epithelial solid tumors.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia A, Mayer IA, Vahdat LT, et al. N Engl J Med. 2019;380:741-751.

FDA Approves TUKYSA® for HER2+ Breast Cancer

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SUMMARY: The FDA on April 17, 2020, approved TUKYSA® (Tucatinib) in combination with Trastuzumab and XELODA® (Capecitabine), for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. 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 will be diagnosed in 2020 and about 42,170 women will die of the disease.

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. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, 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. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

It is estimated that close to 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. Systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy.

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 54 years and patient demographic as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The median duration of follow up in the total treatment population was 14 months. The Primary endpoint was Progression Free Survival (PFS) among the first 480 patients who underwent randomization. Secondary end points assessed in the total treatment population (612 patients) included, Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and safety.

The Primary endpoint of PFS at 1 year was 33.1% in the TUKYSA®-combination group and 12.3% in the placebo-combination group (HR for disease progression or death=0.54; P<0.001), and the median duration of PFS was 7.8 months and 5.6 months, respectively. This represented a 46% reduction in the risk of cancer progression or death in the TUKYSA®-combination group compared to patients who received HERCEPTIN® and XELODA® alone. The Overall Survival at 2 years was 44.9% in the TUKYSA®-combination group and 26.6% in the placebo-combination group (HR for death=0.66; P=0.005), and the median Overall Survival was 21.9 months and 17.4 months, respectively. This represented a 44% reduction in the risk of death in the TUKYSA®-combination group compared to the placebo-combination group. Among the patients with brain metastases, PFS at 1 year was 24.9% in the TUKYSA®-combination group and 0% in the placebo-combination group (HR=0.48; P<0.001), and the median PFS was 7.6 months and 5.4 months, respectively. This represented a 52% reduction in the risk of cancer progression or death in the TUKYSA®-combination group compared to the placebo-combination group. Among the patients with measurable disease at baseline, the confirmed Objective Response Rate was 40.6% in the TUKYSA®-combination group and 22.8% in the placebo-combination group (P<0.001). Common adverse events in the TUKYSA® group included diarrhea, Palmar-Plantar Erythrodysesthesia syndrome, nausea, vomiting and fatigue. Diarrhea and abnormal liver function tests were more common in the TUKYSA®-combination group than in the placebo-combination group.

It was concluded that in heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, the addition of TUKYSA® to HERCEPTIN® and XELODA® resulted in clinically significant improvement in PFS and OS, compared to the placebo-combination group. This trial is unique in that it included patients with active brain metastases, either untreated or progressing.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. Murthy RK, Loi S, Okines A, et al. N Engl J Med 2020;382:597-609.