Tag: Breast Cancer

Primary Breast Tumor Surgery Improves Overall Survival in HER2 Positive 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. Approximately 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 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. Approximately 50% of HER2-positive breast cancers are Hormone Receptor positive. 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. The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

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. A few previously published studies which evaluated the addition of surgical resection of the primary tumor to systemic therapy, among patients with metastatic HER2-positive breast cancer, have provided mixed results, with one study showing improved outcomes. The authors therefore conducted a retrospective study to examine the impact of primary breast tumor resection on survival, in HER2-positive Stage IV breast cancer patients, treated with HER2 targeted therapy.

This retrospective cohort study included records of 3,231 women with HER2 positive Stage IV breast cancer from the National Cancer Database, from 2010 to 2012. Of these women, 89.4% had received chemotherapy/anti-HER2 targeted therapies, 37.7% had received endocrine therapy, 31.8% had received radiation and 25% of the patients had bone only metastasis. Overall, 1,130 women (35%) underwent primary breast tumor resection. The mean age of those who had surgery was 56 years and the Primary endpoints were receipt of surgery and Overall Survival (OS).

At a median follow-up of 21.2 months, the median OS for patients who had surgery was 25 months compared with 18 months for those who did not undergo surgical resection (HR=0.56; P=0.0004). This suggested a 44% reduction in the risk of death with primary breast tumor resection. Patients having Medicare/other government or private insurance, as well as those who received radiation, chemotherapy/anti-HER2 targeted therapies and endocrine therapy were more likely to have surgery. Additionally, Caucasian women were also more likely than non-Hispanic black women, to have surgery. These findings suggested that women with Medicare or private insurance as well as white women were also more likely to have surgery and less likely to die of their disease, than non-Hispanic black women, and those with Medicaid or no insurance.

It was concluded that after controlling for independent variables, surgery of the primary site, in patients with metastatic HER2 positive breast cancer who are managed with present day contemporary treatment, is associated with improved Overall Survival. Breast surgery should therefore be discussed as a part of the treatment strategy, for qualified women, in this patient group. The impact of primary tumor surgery on survival in HER2 positive stage IV breast cancer patients in the current era of targeted therapy. Mudgway R, Chavez de Paz Villaneva C, Lin AC, et al. Presented at AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract 4873.

KISQALI® Improves Overall Survival 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 (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the second leading cause of cancer death in the US. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. The incidence of breast cancer among women under the age of 50 has been increasing by 0.2% per year. Premenopausal breast cancer may be biologically different than post menopausal breast cancer and diagnosis of breast cancer at a young age has been associated with adverse outcomes and less sensitivity to endocrine therapy. Further, premenopausal women are often excluded from hormone therapy trials. The incidence of metastatic disease at the time of diagnosis among patients with Hormone Receptor (HR)- positive breast cancer, has been increasing by about 2% per year.

Cyclin Dependent Kinases (CDK) 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. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) 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 and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, 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 Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-RIBOCICLIB-A-CDK4-and-CDK6-Inhibitor

There are presently three CDK4/6 inhibitors approved by the FDA and they include KISQALI® (Ribociclib), IBRANCE® (Palbociclib) and VERZENIO® (Abemaciclib). All three agents have demonstrated similar, significantly prolonged Progression Free Survival (PFS) when administered in combination with endocrine therapy, as first-line treatment, in women with HR-positive metastatic breast cancer (MONALEESA-2 with KISQALI®, PALOMA-2 with IBRANCE® and MONARCH-3 with VERZENIO®). These trials for the first-line treatment of advanced breast cancer however excluded premenopausal women. The toxicities were slightly different with neutropenia more commonly encountered in the IBRANCE® and KISQALI® studies and diarrhea more often noted with VERZENIO®. KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. It is four times more selective for CDK4 than for CDK6.

The MONALEESA-7 trial is an international, randomized, double-blind, placebo-controlled, Phase III trial in which KISQALI® in combination with endocrine therapy was compared with placebo in combination with endocrine therapy, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer. Patients (N=672) were randomly assigned in a 1:1 ratio, to receive KISQALI® at 600 mg orally once daily for 21 days of each 28 day cycle (N=335), or matching placebo (N=337). Both groups received ZOLADEX® (Goserelin) 3.6 mg administered subcutaneously on day 1 of each 28 day cycle. Patients also received either a nonsteroidal Aromatase Inhibitor (Letrozole 2.5 mg or Anastrozole 1 mg) or Tamoxifen 20 mg, orally once daily continuously. The choice of endocrine therapy was made on the basis of the patient’s previous adjuvant or neoadjuvant therapy or investigator or patient preference. Crossover was not permitted between the two treatment groups. Patients were stratified according to the presence or absence of liver or lung metastases, previous chemotherapy for advanced disease and endocrine therapy. The Primary end point was Progression Free Survival (PFS) and Secondary endpoint included Overall Survival (OS). The superior PFS data with KISQALI® compared to endocrine therapy alone, was previously reported. The authors herein report the results on Overall Survival.

After a median follow up of 34.6 months, the addition of KISQALI® to endocrine therapy resulted in significantly longer Overall Survival, compared to endocrine therapy alone. The estimated OS at 42 months was 70.2% in the KISQALI® group and 46.0% in the placebo group (HR for death=0.71; P=0.00973), suggesting a 29% reduction in the risk of death. No new safety signals were observed and in the KISQALI® group, more instances of QT-interval prolongation were observed in patients who received Tamoxifen than in those who received an Aromatase Inhibitor, but without symptomatic arrhythmias or Torsades de pointes.

It was concluded that KISQALI® along with endocrine therapy significantly prolonged Overall Survival, compared to endocrine therapy alone, among pre and perimenopausal patients with advanced HR-positive, HER2-negative breast cancer and these findings represent a major treatment advance in this patient group. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. Im S-A, Lu Y-S, Bardia A, et al. N Engl J Med 2019; 381:307-316.

US Preventive Services Task Force Recommendations on BRCA Mutation Testing

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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. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the second leading cause of cancer death in the US. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. These mutations can be inherited from either of the parents in an autosomal dominant pattern and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

It is estimated that BRCA1/2 gene mutations occur in approximately 1 in 400 women in the general population and account for 5-10% of breast cancer cases and 15% of ovarian cancer cases. The estimated prevalence of potentially harmful BRCA1/2 mutations is 6% in women with cancer onset before age 40 years, and 2.1% among Ashkenazi Jewish women. Among individuals with a family history of breast or ovarian cancer, BRCA1 mutation prevalence is approximately 13%, BRCA2 mutation prevalence is about 8%, and prevalence of either mutation is about 20%. Mutations in the BRCA1/2 genes increase breast cancer risk by 45-65% by age 70 years. The risk of ovarian, fallopian tube, or peritoneal cancer, increases to 39% for BRCA1 mutations, and 10-17% for BRCA2 mutations.

The US Preventive Services Task Force (USPSTF) in this publication updated the 2013 recommendations on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. These recommendations are based on the evidence of both the benefits and harms of the service and this assessment does not consider the costs of providing a service.

The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery.

Recommendations

1) The USPSTF recommended that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations, with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing.

2) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations.

Risk Assessment

Clinicians should obtain medical and family history specifically inquiring patients about specific types of cancer, primary cancer sites, which family members were affected, whether relatives had multiple types of primary cancer, the age at diagnosis, age at death, and sex of affected family members, both immediate (parents and siblings) as well as more distant (aunts, uncles, grandparents, and cousins). Women who have a family or personal history of breast, ovarian, tubal, or peritoneal cancer should be evaluated by clinicians, to determine the need for in-depth genetic counseling, using appropriate familial risk assessment tools, recognized by the USPSTF. Familial risk assessment factors include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of both breast and ovarian cancer in one individual, male family members with breast cancer, multiple cases of breast cancer in the family, one or more family members with 2 primary types of BRCA-related cancer (such as ovarian cancer), and Ashkenazi Jewish ancestry. Breast cancer risk assessment models such as the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model are not designed to identify BRCA-related cancer risk and should not be used for this purpose.

Genetic Counseling

Genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA1/2mutations, identification of individuals for testing, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options. Genetic counseling should be performed by trained health professionals, including suitably trained primary care clinicians.

Genetic Testing

Testing for BRCA1/2 mutations should be performed only when an individual with history suggesting inherited cancer susceptibility, is willing to talk with a qualified health professional, trained to provide genetic counseling and interpret test results, and when test results will aid in decision-making. BRCA mutation testing should begin with a relative with known BRCA-related cancer, including male relatives, to determine if a clinically significant mutation is detected in the family, before testing individuals without cancer. If an affected family member with a BRCA-related cancer is not available, then the relative with the highest probability of mutation should be tested. Reporting BRCA1/2 mutations identified by genetic tests should include a 5-tier terminology system, using the terms “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.

Treatment and Interventions for women with harmful BRCA1/2 mutations

The USPSTF recommends that clinicians offer intensive screening and risk-reducing medications such as Tamoxifen, Raloxifene, or Aromatase Inhibitors to women at increased risk for breast cancer and at low risk for adverse medication effects. General care for these individuals may include risk-reducing mastectomy and salpingo-oophorectomy.

US Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:652-665.

Adjuvant Treatment with PROLIA® Improves Disease Free Survival 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. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant Aromatase Inhibitors is the standard of care.

ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors that bind reversibly to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase Inhibitors however are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk.Interplay-of-Bone-Formation-and-Bone-Resorption

PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival, by selectively targeting the RANK ligand. The RANK-RANK ligand system is an important mediator of signaling in the genesis of osteoclasts and bone resorption. Additionally, the RANK-RANK ligand system has been implicated in antitumor immunity and may have a role in suppressing tumor agenesis. It has been hypothesized that targeting RANK with anti-RANK inhibitor might reverse the immunosuppressive effect of the RANK-RANK ligand signaling pathway.

ABCSG-18 is a randomized, double-blind, placebo controlled, Phase III trial in which the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 patients enrolled in this study, 3420 patients were randomly assigned 1:1 to receive PROLIA® 60 mg (N=1711) or matching placebo (N=1709), subcutaneously every 6 months, during Aromatase Inhibitor therapy. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA®. The Primary endpoint was the time to first clinical fracture after randomization. The Secondary endpoint was Disease Free Survival (defined as time from randomization to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. The Primary endpoint of the ABCSG-18 trial was met (The Lancet 2015;386:433-443) and the use of PROLIA® as an adjuvant to Aromatase Inhibitor therapy significantly delayed time to first clinical fracture, compared to Placebo (HR=0.50; P<0.0001). The authors in publication reported the Secondary endpoint of Disease Free Survival (DFS) outcomes from this study.

After a median follow-up of 73 months, there was a significant improvement in the Disease Free Survival among patients in the PROLIA® group compared to the placebo group (HR=0•82; P=0.026). In the PROLIA® group, the DFS was 89.2% at 5 years and 80.6% at 8 years of follow-up, compared with 87.3% at 5 years and 77.5% at 8 years in the placebo group. The total number of adverse events was similar in the PROLIA® and placebo groups and there were no reported cases of osteonecrosis of the jaw bone or atypical femoral fractures.

It was concluded that PROLIA® constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving Aromatase Inhibitor therapy, with a Disease Free Survival benefit similar to bisphophonates, but with a better toxicity profile and convenient subcutaneous injections twice yearly. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Gnant M, Pfeiler G, Steger GG, et al. Lancet Oncol 2019;20:339-351

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for 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. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

Oncotype Dx assay categorizes patients on the basis of Recurrence Scores into Low risk (less than 18), Intermediate risk (18-30), and High risk (31 or more). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer. In this study, the Intermediate risk Recurrent Score (18-30) was changed to 11-25, to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for under treatment.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. Patients were followed up for 9 years. The Primary endpoint was invasive Disease Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. Results reported in June 2018 showed that while most women with an Intermediate Recurrence Score of 11-25 did not benefit from chemotherapy, women 50 years or younger with a Recurrence Score of 16-25 did indeed benefit from adjuvant chemotherapy.

The authors in this publication provided additional results from the same data set showing that adding “Clinical Risk” provides additional prognostic information. The investigators used a binary classification system from the MINDACT trial (Microarray in Node-Negative Disease May Avoid Chemotherapy), which used a 70-gene assay, and divided patients into high or low “Clinical Risk” based on tumor size and histologic grade. Clinical Risk was defined as low if the tumor was 3 cm or less in diameter and had a low histologic grade, 2 cm or less and had an intermediate histologic grade, or 1 cm or less in diameter and had a high grade. The Clinical Risk was defined as high if the low-risk criteria were not met. This additional reporting provided prognostic information about recurrent risk, but not benefits of chemotherapy particularly in the Intermediate Recurrence Score group.TAILORx-HR-Positive-HER-Negative-Early-Stage-Breast-Cancer

Among women who were 50 years of age or younger with a low Recurrence Score, the distant recurrence rate at 9 years was less than 5%, irrespective of Clinical Risk, and about 5% among those with an intermediate Recurrence Score with low Clinical Risk. However in sharp contrast, among women 50 years of age or younger, with high Clinical Risk and an intermediate Recurrence Score who had received endocrine therapy alone, the rate of distant recurrence at 9 years was 12.3%, compared with 6.1% among women who had received adjuvant chemotherapy. It is possible that younger women with a Recurrence Score of 11-25 and high Clinical Risk, receiving endocrine therapy alone, may have been undertreated with Tamoxifen, and the authors speculated that based on previously published studies, adding Ovarian Suppression and an Aromatase Inhibitor might result in risk reduction, equivalent to that observed using adjuvant chemotherapy.

The authors concluded that these new findings complement the original, definitive TAILORx conclusion and integration of genomic (Recurrence Score) and Clinical Risk may provide a more accurate estimate of prognosis for individual patients, than could be provided by either the genomic or clinical information alone. They added that this Clinical Risk stratification facilitates more refined estimates of absolute chemotherapy benefit for women 50 years of age or younger, with a Recurrence Score 16-25. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. Sparano JA, Gray RJ, Ravdin PM, et al. N Engl J Med 2019;380:2395-2405

Prognostic Value of Progesterone Receptor in Estrogen Receptor-Positive, HER-2 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 (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors (ER) and/or Progesterone Receptors (PR) and these patients are often treated with anti-estrogen therapy.

It has been well established that the detection of Estrogen, Progesterone and HER-2 neu receptors on the tumor cell expressed either alone or together, is a significant prognostic factor, and is associated with the conditional gene expression in the tumor cell itself. The St. Gallen International Expert Consensus in 2011 classified breast cancer into five molecular subtypes with prognostic significance, based on these genetically determined expressions in the tumor cell. The five molecular subtypes of breast cancer include 1) Luminal A (ER+ and/or PR+, HER-2 negative, Ki-67 less than 14%) constituting about 26% of patients 2) Luminal B with HER-2 negative (ER+ and/or PR+, HER-2 negative, Ki-67 14% or more) constituting about 32% 3) Luminal B with HER-2 positive (ER+ and/or PR+, HER-2+, any Ki-67) constituting about 25% 4) HER-2 enriched (ER-, PR-, HER-2+) accounting for about 8% of patients 5) Basal-like (triple negative) (ER-, PR-, HER-2 negative, CK5/6+ and/or EGFR+) constituting about 9% of all breast cancer patients. According to the 2015 St. Gallen guidelines, adjuvant chemotherapy can avoided in Luminal A patients, whereas patients with ER+ HER-2 negative tumors with low or no PR expression or with high Ki-67 expression are considered to have a high risk of relapse and adjuvant chemotherapy is often recommended. It should be noted however that low PR expression in Luminal A patients can carry a poor prognosis as well.

The Progesterone Receptor (PR) is a member of the nuclear receptor family and is regulated by the Estrogen Receptor. It is expressed in over two-thirds of ER-positive breast cancers and is more highly expressed in the Luminal A breast cancer subtype. Several studies have demonstrated improved prognosis among PR-positive breast cancer patients. Further, in ER+, HER-2 negative breast cancers, the Progesterone Receptor is an independent prognostic marker. However, the prognostic value of PR by tumor grade has been unclear.

The authors hypothesized that patient with high-grade tumors might do well if PR is positive. The objective of this study therefore was to study the prognostic value of PR in tumors with high tumor proliferative index, using tumor grade as a surrogate for the proliferative activity of ER+, HER-2 negative breast cancer. This retrospective study included women with primary operable, invasive, ER+ HER-2 negative breast cancer, diagnosed between 2000 and 2012, treated at University Hospitals Leuven. The association of PR status and subtype (Grade 1-2 versus Grade 3) was assessed with Distant Recurrence Free Interval (DRFI) and Breast Cancer specific survival. The data set from BIG 1-98 trial was used for validation. A total of 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. The median patient age was 58 years, 73% had Luminal A-like subtype, 27% had Luminal B-like subtype, lymph node status was predominantly negative (62%) and PR was positive in 89% of patients. Median tumor size was 2.1 cm and most of the patients received adjuvant endocrine therapy (96%) and/or radiotherapy (87%). Adjuvant chemotherapy was administered to 29% of the patients. The median follow up period was 8.6 years.

It was noted in this study that PR positive tumors were more strongly associated with better prognosis in Luminal B-like than in Luminal A-like breast cancer, suggesting that PR is more prognostic in Luminal B-like versus Luminal A-like tumors. Among the Luminal B-like tumors, the 5-year cumulative incidences of distant recurrence were 18.7% in PR negative and 9.2% in PR positive tumors. 

It was concluded PR positivity may be more protective against metastatic relapse in Luminal B-like versus Luminal A-like breast cancer. An absent PR is a clinically more important negative prognostic factor in tumors with a high proliferative index than in low proliferative ER+ HER-2 negative breast tumors. Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer. Van Astena K, Slembroucka L, Olbrecht S, et al. The Oncologist 2019;24:165-171

FDA Approves First PI3K Inhibitor, PIQRAY®, for Breast Cancer

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SUMMARY: The FDA on May 24, 2019 approved PIQRAY® (Alpelisib) in combination with FASLODEX® (Fulvestrant), to treat postmenopausal women and men, with Hormone Receptor (HR) positive, Human Epidermal growth factor Receptor 2 (HER2) negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test), following progression on or after an endocrine-based regimen. The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing. 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 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors 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.Alpelisib - Mechanism-of-Action

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.

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. SOLAR-1 clinical trial, which was conducted to test this hypothesis, became the basis for this FDA approval.

SOLAR-1 is a global, double-blind, placebo-controlled, randomized phase III trial, which studied the benefit of PIQRAY® in combination with FASLODEX® (Fulvestrant) among postmenopausal women and men with PIK3CA-mutated HR+/HER2 negative advanced or metastatic breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor. In this study, 572 patients were randomized in a 1:1 ratio to receive PIQRAY® 300 mg orally daily or placebo once daily, in combination with FASLODEX® 500mg IM on days 1 and 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were stratified based on visceral metastases and prior CDK4/6 inhibitor treatment. A total of 341 patients had PIK3CA mutations upon testing of the tumor tissue with 169 patients receiving the PIQRAY® combination and 172 patients receiving FASLODEX® alone. Enrolled patients had received one or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. They had not previously received FASLODEX® or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. Approximately half of the patients in each treatment group had lung or liver metastases and 6% had received prior CDK4/6 inhibitor therapy. The Primary endpoint was Progression Free Survival (PFS) for patients with the PIK3CA mutation. Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate, Health-Related Quality of Life, Efficacy in PIK3CA non-mutant cohort, Safety and Tolerability.

The Primary endpoint was met and at a median follow up of 20 months, the PFS was nearly twice as long in patients with PIK3CA mutations randomized to PIQRAY® plus FASLODEX® compared to the placebo plus FASLODEX® group. The median PFS was 11.0 months in the PIQRAY® group compared to 5.7 months in the placebo group (HR=0.65; P=0.00065). In patients with measurable, PIK3CA-mutated advanced breast cancer (N=262), the Overall Response Rate was 36% for the PIQRAY® plus FASLODEX® group versus 16% for placebo plus FASLODEX® group (P=0.0002). There was no significant PFS benefit noted in the PIK3CA-nonmutant patient group receiving PIQRAY® plus FASLODEX® The most frequent toxicities with PIQRAY® were hyperglycemia which could be managed with Metformin, nausea, decreased appetite and skin rash.

It was concluded that PIQRAY® given along with FASLODEX® significantly improved Progression Free Survival compared to Placebo plus FASLODEX® with manageable toxicities. The authors commented that this is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in PIK3CA-mutated HR+, HER2 negative advanced breast cancer, highlighting the importance of clinical genomics in advanced breast cancer. PIQRAY® is also the first novel drug approved under the Real-Time Oncology Review pilot program. It however remains unclear whether PIQRAY® should be incorporated into the current treatment paradigm upfront, along with endocrine therapy and a CDK 4/6 inhibitor, or sequentially following disease progression on a combination of endocrine therapy and a CDK 4/6 inhibitor. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. André F, Ciruelos EM, Rubovszky G, et al. Presented during the Presidential Symposium 1 at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3_PR.

PIQRAY® (Alpelisib)

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The FDA on May 24, 2019 approved PIQRAY® in combination with FASLODEX® (Fulvestrant) for postmenopausal women, and men, with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test following progression on or after an endocrine-based regimen. PIQRAY® is a product of Novartis Pharmaceuticals Corporation.

FDA Approves KADCYLA® for Early Breast Cancer

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SUMMARY: The FDA on May 3, 2019, approved KADCYLA® (Ado-Trastuzumab Emtansine) for the adjuvant treatment of patients with HER2-positive early breast cancer, who have residual invasive disease after neoadjuvant Taxane and HERCEPTIN® (Trastuzumab)-based treatment. 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 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 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. 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. Mechanism-of-Action-KADCYLA

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. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.

It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response 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 evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

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 majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival (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). The median duration of follow up was 41.4 months in the KADCYLA® group and 40.9 months in the HERCEPTIN® group.

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. Invasive Disease Free Survival, 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%. Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the KADCYLA® group and in 15.9% of the HERCEPTIN® group. A consistent benefit was seen across all prespecified subgroups. Adverse events were consistent with the known safety profile of KADCYLA®, with more toxicities associated with KADCYLA® than with HERCEPTIN®. Additional follow-up will be necessary to determine the Overall Survival benefit with adjuvant KADCYLA®.

It was concluded that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, substituting KADCYLA® for adjuvant HERCEPTIN® reduced the risk of recurrence of invasive breast cancer or death by 50%, with the benefit seen across all patient subgroups. The authors added that even though KATHERINE trial focused on higher-risk patients with residual invasive breast cancer after completion of neoadjuvant chemotherapy, CNS recurrence remains a persistent problem. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. N Engl J Med 2019;380:617-628

KADCYLA® (Ado-trastuzumab Emtansine)

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The FDA on May 3, 2019, approved KADCYLA® for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC), who have residual invasive disease after neoadjuvant Taxane and HERCEPTIN® (trastuzumab)-based treatment.KADCYLA® is a product of Genentech, Inc.

Patients should be selected based on an FDA-approved companion diagnostic for KADCYLA®. FDA also approved both the Ventana Medical Systems, Inc. PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and the INFORM HER2 Dual ISH DNA Probe Cocktail assay as companion diagnostic devices for selecting patients.