Tag: Breast Cancer

Late Breaking Abstract – ASCO 2023: Adjuvant Treatment with Ribociclib in Early 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

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. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant Endocrine Therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.

NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Safety, Quality of Life, and Overall Survival.

At a median follow up of 34 months, as of data cutoff, 74.7% of patients remained on study treatment, with 1,984 patients on Ribociclib and 1,826 patients on Endocrine Therapy alone. The addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%. The 3-year invasive DFS rates were 90.4% in the Ribociclib group, compared with 87.1% in the Endocrine Therapy alone. This invasive DFS benefit was generally consistent across stratification factors and other subgroups. There was a trend towards improvement in Overall Survival with the addition of Ribociclib, although further follow up is needed. This regimen had a favorable safety profile with no new safety signals.

It was concluded from this study that the addition of Ribociclib to Endocrine Therapy demonstrated a statistically significant, clinically meaningful improvement in invasive Disease Free Survival, with a well-tolerated safety profile. The authors added that this study results support the addition of Ribociclib to Endocrine Therapy as the treatment of choice in a broad group of patients with Stage II or III HR+/HER2-negative early breast cancer, including those with high risk node negative disease. The lower dose of Ribociclib chosen in this study and given over an extended 3-year period may be important to prolong cell cycle arrest and drive more tumor cells into senescence or death.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. DOI: 10.1200/JCO.2023.41.17_suppl.LBA500 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA500-LBA500.

Capivasertib in Advanced Hormone Receptor Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is HR-positive, HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR-positive, HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. A therapy overcoming endocrine resistance is an area of active research in the breast cancer space.

The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is overactivated. Inhibition of the PI3K/Akt signaling pathway leads to inhibition of cell proliferation and induction of apoptosis in tumor cells. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. Overactivation of the PI3K-AKT-PTEN signaling pathway occurs in approximately 50% of HR-positive, HER2-negative breast cancers by means of activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN. These alterations may be present at the time of cancer recurrence, and can also be acquired following previous treatment including with CDK4/6 inhibitors. Further, AKT signaling may also be activated in the absence of genetic alterations in patients with endocrine resistance.

Capivasertib is a novel, first-in-class, orally bioavailable small molecule inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy, for a variety of human cancers. In the Phase II FAKTION trial, Capivasertib in combination with Fulvestrant significantly improved Progression Free and Overall Survival as compared with Fulvestrant alone, among postmenopausal women with HR-positive advanced breast cancer, who had previously received endocrine therapy. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor and CDK4/6 inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease, and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant, and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or have become resistant to endocrine therapies and CDK4/6 inhibitors.

Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. Turner N, Oliveria M, Howell SJ, et al., for the CAPItello-291 Study Group. N Engl J Med 2023; 388:2058-2070.

Pathologic Complete Response and Individual Patient Prognosis after Neoadjuvant Chemotherapy Plus Anti-HER2 Therapy in Early 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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.

Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (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. In a comprehensive meta analysis by Spring L., et al. (Clin Cancer Res. 2020;26:2838-2848), in the subgroup of HER2-positive patients (N= 5,711), an association between pCR and both EFS and OS could be observed. With the availability of different post-neoadjuvant treatments in the HER2-positive treatment setting, it is important and relevant to define patients with increased risk of relapse, despite the achievement of pCR.

The rationale for this study was to characterize the prognostic role of pCR (pathological Complete Response) in patients with HER2-positive early breast cancer, and whether clinical factors, such as Tumor stage, Nodal involvement, and Hormone Receptor status, had prognostic relevance in patients with HER2-positive early breast cancer, with and without pCR, following neoadjuvant systemic treatment with chemotherapy plus anti-HER2 therapy.

The present analysis included individual data from 3710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive early breast cancer. The following trials were included: CHERLOB, GeparQuattro, GeparQuinto, GeparSixto, HANNAH, LAPATAX, NEOALTTO, NEOSPHERE, NOAH, NSABP B-41, and TRYPHAENA. Each of these trials had 100 or more patients enrolled, and data was available for pCR, Event Free Survival (EFS), and Overall Survival (OS) after a follow up of 3 or more years. The definition of pCR used for the current analysis was the absence of residual invasive cancer in the resected breast specimen and all sampled ipsilateral lymph nodes, but allowing for in situ cancer (ypT0/Tis ypN0). Across trials, median age was 49 years, and 56.7% of patients were diagnosed with Tumor stage cT1-2. Nodal involvement was present at diagnosis in 64.9% of patients, and 54.9% were Hormone Receptor-positive. The median follow up across trials was 61.2 months. The objective of this study was to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy and anti-HER2 therapy.

Across trials, approximately 40.4% of patients had a pCR and 59.6% had residual disease after neoadjuvant therapy. A pCR occurred more often in patients with T1-2 tumors, absence of Nodal metastases, and Hormone Receptor-negative disease. Patients experiencing a pCR were at lower risk of disease recurrence or death regarding EFS (HR=0.39; P<0.001) and had a significantly better OS (HR=0.32; P<0.001).

In patients who had a pCR, clinical T stage (cT1-2 versus cT3-4) and clinical N stage (cN0 versus cN+) status were independent prognostic factors for EFS, but only clinical T stage was significantly prognostic for OS, identifying patients at higher risk of relapse despite pCR . By contrast, in patients without pCR and with residual disease, clinical T stage, clinical N stage and Hormone Receptor status were independent prognostic factors for EFS as well as OS. For patients not having a PCR, risk factors included the presence of T3-4 tumors, clinical Node Positive disease or Hormone Receptor-negative status.

The authors concluded that patients achieving pathological Complete Response have better survival outcomes than patients who do not. Nonetheless, Tumor size and Nodal status remain important poor prognostic features even after a pathologic Complete Response and adjuvant therapy in pathological Complete Response patients should not be attenuated.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti–Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer. van Mackelenbergh MT , Loibl S , Untch M, et al., on behalf of the CTNeoBC project. J Clin Oncol 2023; 41:2998-3008

Breast-Conserving Surgery with or without Irradiation in Early 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. 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. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years and approximately 26% of breast cancer diagnoses are in women 65 to 74 years of age. Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and is associated with acute and late toxicities. Avoidance of radiation in elderly patients with low risk disease has remained controversial due to the lack of long term Level 1 evidence. In the LUMINA trial and PRIME II study of women over 55 years of age with low risk breast cancer, after a median follow up of 5 years, 5-year rate of ipsilateral breast tumor recurrence was low at 2-4% among those women who did not receive adjuvant whole-breast radiotherapy after breast-conserving surgery. The researchers herein reported the 10-year outcomes of the PRIME II trial.

PRIME II is a Phase III randomized clinical trial of the omission of breast irradiation, designed by the Scottish Cancer Trials Breast Group (SCTBG). This study included women 65 years of age or older, who had Hormone Receptor (HR)-positive, node-negative, T1 or T2 primary breast cancer (with tumors 3 cm or less in the largest dimension), treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were eligible if they had either cancer with Grade 3 histologic features or lymphovascular invasion but not both. A total of 1326 women were randomly assigned to receive 40-50 Gy whole-breast irradiation (N=658) or no radiation therapy (N=668). Both treatment groups were well balanced. The median patient age was 70 years and less than 10% of patients had ER-low tumors. The Primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and Overall Survival were also assessed. The median follow up was 9.1 years.

The cumulative incidence of local breast cancer recurrence after 10 years of follow up was 9.5% in the no-radiotherapy group and 0.9% in the radiotherapy group (HR=10.4; P<0.001). Even though local recurrence was more common in the group that did not receive radiotherapy, there was no substantial difference in the 10-year incidence of distant recurrence as the first event between the two treatment groups (1.6% without radiotherapy and 3.0% with radiotherapy). Overall Survival at 10 years was almost identical in the two groups, at 80.8% with no radiotherapy and 80.7% with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.

The authors concluded that omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event, or Overall Survival, among women 65 years of age or older, with Grade 1 or 2, Estrogen Receptor-high breast cancers, treated with breast-conserving surgery and 5 years of adjuvant endocrine therapy.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. Kunkler IH, Williams LJ, Jack WJL, et al. N Engl J Med 2023; 388:585-594.

Interrupting Endocrine Therapy to Attempt Pregnancy after 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. 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. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receive modern adjuvant endocrine therapy and have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing. Pregnancy is contraindicated during endocrine therapy and a delay in pregnancy for 5-10 years can further reduce the chance of a subsequent live birth due to age related declines in fertility.

The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial is a multicenter, global, single-arm prospective study, designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy is associated with a higher risk of breast cancer recurrence. This study included 516 women with Stage I-III Hormone Receptor (HR)-positive early breast cancer, 42 years or less, who had received 18-30 months of adjuvant endocrine therapy and wished to interrupt endocrine therapy for pregnancy. The study permitted treatment interruption for up to 2 years (after a 3 month endocrine therapy washout period) to allow pregnancy, delivery and breastfeeding, followed by endocrine therapy resumption to complete the planned duration of 5-10 of adjuvant endocrine therapy. The median time from breast cancer diagnosis to enrollment was 29 months. The median age was 37 years, 75% were nulliparous, fertility preservation was used by 51% of women, 93% had Stage I/II disease, 66% were node negative and 62% had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed endocrine therapy (42%), followed by Tamoxifen plus Ovarian Function Suppression (OFS) (35%).

The Primary endpoint of the study was Breast Cancer-Free Interval (BCFI), defined as the time from study enrollment to the first invasive breast cancer event (local/regional/distant recurrence or contralateral breast cancer). Three interim safety analyses were conducted by a Data Safety Monitoring Committee, and determined that the trial would be suspended if there were more than 46 breast cancer recurrences within approximately 3 years of average follow-up. This threshold however was not reached.

At a median follow up of 41 months, of the 497 patients evaluated for pregnancy status, 74% (N=368) had at least one pregnancy, with 70% of the pregnancies occurring within 2 years. Additionally, 63.8% (N=317) had at least one live birth, with a total of 365 babies born. Birth defects were low at 2% and the rates of conception and childbirth were similar to rates in the general public. The 3-year breast cancer recurrence rate among patients who halted therapy was 8.9%, similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials, which examined adjuvant endocrine therapy in premenopausal patients. Long term follow up is ongoing to assess recurrence risk over time, and trial participants were strongly recommended to resume endocrine therapy following their pregnancy attempts or success.

The authors concluded that among select women with previous Hormone Receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. These data provide guidance to younger patients diagnosed with early breast cancer on endocrine therapy, who may be hoping to have children, and such decisions should be made in close consultation with health professionals.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. Partridge AH, Niman SM, Ruggeri M, et al., for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. N Engl J Med 2023; 388:1645-1656.

HER2DX Genomic Assay Predicts Pathological Response in Early Stage HER2-Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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. Patients with HER2-positive 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.

HERCEPTIN® (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. PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie., HER3, HER1 and HER4. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways, which has been attributed to differing mechanisms of action and synergistic interaction.

In the NeoSphere Phase II trial, among patients with locally advanced, inflammatory, or early HER2-positive breast cancer, the addition of Pertuzumab to Trastuzumab and Docetaxel led to a statistically significant and clinically meaningful 16.8% increase in pathologic Complete Response rate (pCR) in the breast and a 17.8% increase in total pCR in the breast and axilla. Further, the addition of one year of Pertuzumab to Trastuzumab-based chemotherapy improved invasive Disease Free Survival, but this benefit was restricted to patients with node-positive disease and no Overall Survival benefit was observed. The benefits of Pertuzumab in early-stage HER2-positive disease were modest. Biomarkers beyond HER2 status are therefore needed, to guide the use of Pertuzumab in the treatment of early-stage HER2-positive breast cancer.

HER2DX (Reveal Genomics) is a novel clinically available genomic test that measures the expression of 27 genes from Formalin-Fixed, Paraffin-Embedded (FFPE) breast cancer tissues. This assay integrates biologic information such as Immune infiltration, luminal differentiation, tumor cell proliferation and HER2 amplicon expression from 4 gene signatures, with clinical data such as tumor stage and nodal stage.

The present study was conducted to determine if the use of HER2DX genomic assay in pretreatment baseline tissue samples of patients with early-stage ERBB2-positive breast cancer, predicted response to neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab. This analysis is a retrospective, multicenter, observational study conducted in Spain from 2018 to 2022. In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts, with results from the assay (DAPHNe and I-SPY2) was performed. All patients had Stage I-III ERBB2 (HER2) positive breast cancer, and clinical T1- T2 and node-positive disease was present in 72.9% and 63.9% patients, respectively, and 67.7% tumors were hormone receptor positive. The mean age was 50 years and all patients had Formalin-Fixed Paraffin-Embedded tumor specimens available prior to starting therapy. Patients received Trastuzumab, 8 mg/kg IV as a loading dose, followed by 6 mg/kg IV every 3 weeks in combination with Docetaxel, 75 mg/m2 IV every 3 weeks and Carboplatin AUC of 6 IV every 3 weeks for 6 cycles, or this regimen plus Pertuzumab, 840 mg IV as a loading dose, followed by an 420 mg IV every 3 weeks for 6 cycles. HER2DX genomic assay was evaluated in 155 patients with ERBB2-positive breast cancer. The main outcome measures were the association of baseline assay-reported pathologic Complete Response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to Pertuzumab.

The overall pCR rate was 57.4%. The assay-reported pathologic Complete Response (pCR) score showed statistically significant association with pCR in the breast and axilla following Trastuzumab-based chemotherapy independent of Pertuzumab use. The pCR rates in the breast and axilla in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (Odds Ratio=7.85; P<0.001). In the combined analysis of DAPHNe and I-SPY2 trials (N=282), assay-reported pCR-high tumors had an increase in pCR rate in the breast and axilla with the use of Pertuzumab (Odds Ratio=5.36; P<0.001), and this benefit was not seen in the assay-reported pCR-low tumors (Odds Ratio=0.86; P=0.77). A statistically significant interaction was observed between the assay-reported pCR score and the effect of Pertuzumab on pCR in the breast and axilla.

It was concluded that HER2DX genomic assay provides clinically meaningful information to guide therapeutic decisions, and can predict pCR following neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab, independent of known clinical-pathological variables and intrinsic subtype. This assay could guide therapeutic decisions regarding the use of neoadjuvant Pertuzumab and can reliably identify patients who might be ideal candidates for neoadjuvant taxane, Trastuzumab and Pertuzumab.

Assessment of a Genomic Assay in Patients With ERBB2-Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy With or Without Pertuzumab. Bueno-Muiño C, Echavarría I, López-Tarruella S, et al. JAMA Oncol. Published online April 27, 2023. doi:10.1001/jamaoncol.2023.0187

ORSERDU® for ESR-1 Mutated 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 (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

Fulvestrant (FASLODEX®) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

ORSERDU® (Elacestrant) is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by ORSERDU® in the HR-positive xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, ORSERDU® was noted to have an acceptable safety profile and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with HR-positive metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=239). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

This study met both co-Primary endpoints and treatment with ORSERDU® resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care treatment. In the group of patients whose tumors had ESR1 mutations, the median PFS was 3.8 months in the ORSERDU® group and 1.9 months in the Standard of Care group (HR=0.55; P=0.0005), reducing the risk of progression or death by 45%. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6 inhibitors usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months in the ORSERDU® group versus 1.9 months in the Standard of Care group, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6 inhibitors for at least 12 months.

It can be concluded from this study that ORSERDU® is the first oral Selective Estrogen Receptor Degrader for ER-positive, HER2-negative advanced breast cancer patients with ESR1 mutations, and offers a novel therapeutic option for this patient group.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. J Clin Oncol, 1;40(28):3246-3256. DOI:10.1200/JCO.22.00338.

 

FDA Approves TRODELVY® for HR-Positive Breast Cancer

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SUMMARY: The FDA on February 3, 2023, approved TRODELVY® (Sacituzumab govitecan-hziy) for patients with unresectable, locally advanced or metastatic Hormone Receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer, who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

TRODELVY® (Sacituzumab govitecan) 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. TRODELVY® was approved by the FDA in 2021 for patients with unresectable, locally advanced or metastatic Triple Negative Breast Cancer, who have received two or more prior systemic therapies, at least one of them for metastatic disease.

In the IMMU-132 Phase I/II TRODELVY® study, the Hormone Receptor positive (HR+)/HER2-negative cohort of patients with metastatic breast cancer patients had an Objective Response Rate (ORR) of 31.5%, median Progression Free Survival (PFS) of 5.5 months and median Overall Survival (OS) of 12 months, with manageable toxicities.

The present new FDA approval is based on TROPiCS-02, a global, open-label, randomized, Phase III study, conducted to confirm the benefit of TRODELVY® in HR+/HER2- negative advanced breast cancer. In this study, 543 patients with HR+/HER2-negative, unresectable, locally advanced or metastatic breast cancer, were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on D1 and 8, every 21 days (N=272), or treatment of physician’s choice, which included single agent treatment with either Capecitabine, Eribulin, Vinorelbine, or Gemcitabine (N=271). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Eligible patients had 3 median prior chemotherapy regimens for metastatic breast cancer, and one prior therapy for metastatic breast cancer was allowed if disease progressed in 12 months or less after neoadjuvant chemotherapy. Patients were required to have received endocrine therapy, a CDK4/6 inhibitor and at least one prior therapy with a Taxane in any setting. Majority of patients had visceral metastases (95%), 86% had prior endocrine therapy for metastatic breast cancer for at least 6 months, and 60% and 38% received prior CDK4/6 inhibitors for 12 months or less, and for more than 12 months, respectively. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review and key Secondary endpoint was Overall Survival (OS).

The median Progression Free Survival was 5.5 months with TRODELVY® versus 4 months with standard chemotherapy (HR=0.66; P=0.0003), representing a 34% improvement in PFS with TRODELVY®. This benefit was seen across all treatment subgroups including those who were 65 years or older, those who were heavily pretreated, as well as those with visceral metastases. The authors reported the planned TROPiCS-02 Overall Survival data at the 2nd interim analysis.

At a median follow up of 12.5 months, TRODELVY® significantly improved median Overall Survival compared to standard chemotherapy (14.4 months versus 11.2 months; HR=0.79; P=0.02). The Objective Response Rate (ORR) was 21% with TRODELVY® versus 14% with standard chemotherapy, and the median Duration of Response was 8.1 months versus 5.6 months, respectively. Treatment with TRODELVY® also resulted in an overall Health-Related Quality of Life benefit over chemotherapy, with delayed deterioration in fatigue and global health score/ Quality of Life. Grade 3 or more adverse events were observed in 74% of patients receiving TRODELVY® and in 60% of those receiving chemotherapy, and the most common toxicities associated with TRODELVY® were diarrhea neutropenia, nausea, alopecia and fatigue.

It was concluded from this landmark analysis that treatment with TRODELVY® resulted in a statistically significant and clinically meaningful improvement in Progression Free Survival, Overall Survival, Objective Response Rate and Quality of Life, compared to standard chemotherapy, in heavily pre-treated patients with HR+/HER2-negative, endocrine-resistant, unresectable, locally advanced or metastatic breast cancer. TRODELVY® should therefore be considered as a new treatment option for this patient population.

Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HR+/HER2– metastatic breast cancer. Rugo HS, Bardia A, Marmé F, et al: ESMO Congress 2022. Abstract LBA76. Presented September 9, 2022.

Capivasertib Plus Fulvestrant Improves Progression Free Survival in Advanced Hormone Receptor Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is HR-positive, HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. Therapies overcoming this resistance is an area of active research in the breast cancer space.

Capivasertib is a novel pyrrolopyrimidine derivative, and is first-in-class orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy for a variety of human cancers. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.

Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Turner N, Oliveria M, Howell SJ, et al. Presented at the 2022 San Antonio Breast Cancer Symposium: December 6-10, 2022; San Antonio, TX. Abstract GS3-04.