Tag: Breast Cancer

Adjuvant KADCYLA® Superior to HERCEPTIN® in High Risk 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. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) 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.Mechanism-of-Action - KADCYLA

The present study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy. These high risk patients have an unfavorable prognosis, compared to those who have no residual cancer following neoadjuvant 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® 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 was 50%, with the benefit seen across all patient subgroups. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. (published online December 5, 2018). New Engl Jour Med. doi: 10.1056/NEJMoa1814017

TALZENNA® (Talazoparib)

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The FDA on October 16, 2018 approved TALZENNA®, a poly (ADP-ribose) polymerase (PARP) inhibitor, for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2 negative, locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for TALZENNA®. TALZENNA® is a product of Pfizer Inc.

Testing for BRCA1 and BRCA2 Mutations May Not Be Adequate in Breast Cancer Patients

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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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and 40,920 women are expected to die from the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers.These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

Breast cancer patients have a 5-12% lifetime risk of a second primary cancer. It remains unclear however whether patients with breast cancer and another primary cancer have mutations in genes other than BRCA1 and BRCA2, compared to those with a single breast cancer. There are well established data on the cancer risks, associated with different gene mutations. The authors hypothesized that among these patients, a number of factors including environmental exposures and genetic predisposition, may play a role in the development of more than one primary cancer in their lifetime. Recently published study suggested that there was a 85% cumulative breast cancer risk by age 60 years, among those with mutations in the TP53 gene (Cancer2016;122(23):3673-3681). Further with the increasing recognition that germline mutations in genes may have clinical and treatment implications, majority of patients are feeling comfortable opting for upfront multiple genetic mutation testing.

The researchers in this study looked at a panel of 15 actionable mutations beyond BRCA and the gene panel included TP53, PALB2, CDH1, PTEN, STK11, CHEK2, ATM, NBN, MSH6, PMS2, MSH2, MLH1, CDKN2A, MUTYH monoallelic, and CHEK2 Low Risk. Two cohorts of BRCA1 and BRCA2 negative patients were studied. The first cohort included high-risk breast cancer patients with either a single breast cancer (N=464) or breast cancer and an additional primary cancer (N=551). The second cohort comprised of patients with familial breast cancer (inherited risk) with either a single breast cancer (N=1464) or breast cancer and another primary cancer (N=340).

In a total of 891 patients in both cohorts who had breast cancer and an additional primary cancer, there was twice the risk of inheriting mutations in genes other than BRCA1 and BRCA2. In cohort 1, the mutation rate among patients who had breast cancer and an additional primary cancer was 8.7% compared to 4.1% among those with single breast cancer (P=0.003) and in cohort 2, the mutation rate was 8.2% versus 4.2%, respectively (P=0.003).

There was however a differences in individual gene mutation rates between the two cohorts. Among patients with breast cancer and an additional primary cancer in cohort 1, mutations in TP53 and MSH6 were significantly higher, whereas among the patients in cohort 2 with familial breast cancer, mutations in ATM, CHEK2 and PALB2 were significantly higher both in those with breast cancer and another primary cancer and those with a single breast cancer.

The authors concluded that patients with multiple primary cancers should be offered multiplex panel testing to identify patients at risk. Identifying mutations, especially mutations in the TP53 gene may have a bearing on appropriate recommendations such as risk-reducing bilateral mastectomy or mastectomy instead of a lumpectomy in this patient group. Thus, risk assessment using multiple genetic testing panels can be beneficial for clinical care and surveillance. Inherited mutations in breast cancer patients with and without multiple primary cancers. Maxwell KN, Vijai V, Lilyquist J, et al. DOI: 10.1200/JCO.2018.36.15_suppl.1503 Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 1503-1503.

ASCO Endorses Complementary Therapy Guidelines for Breast Cancer Patients

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SUMMARY: The American Society for Clinical Oncology (ASCO) after careful review, endorsed the Society for Integrative Oncology (SIO) guideline on the use of integrative therapies during and after breast cancer treatment. Integrative medicine is defined as a patient-centered, evidence-informed field of care that uses mind and body practices, natural products, and/or lifestyle modifications to improve health, quality of life, and clinical outcomes. The ASCO Expert Panel determined that the recommendations in the SIO guideline published in 2017 are clear, thorough, and based on the most relevant scientific evidence. The panel emphasized that these therapies are complementary and should be used along with conventional anticancer treatment, thereby taking a more comprehensive treatment approach across the cancer care continuum, to manage symptoms and adverse effects of breast cancer treatment. This ASCO guideline excluded lifestyle changes such as diet and exercise, mainstream interventions such as support groups, and practices like attention-restoration therapy, that are still being evaluated. Practices such as prayer and spirituality were not considered specifically integrative oncology therapy.

Guideline Question

What are evidence-based approaches to the use of integrative therapies in the management of symptoms and adverse effects during and after breast cancer treatment?

Target Population

Patients undergoing treatment of breast cancer and survivors of breast cancer

Target Audience

Oncologists, integrative medicine providers, supportive care specialists, nurses, pharmacists, primary care providers, and patients with breast cancer

Recommendation-Grading-System

Key Recommendations

Acute Radiation Skin Reaction

Aloe vera and hyaluronic acid cream should not be recommended for improving acute radiation skin reaction. (Grade D)

Anxiety and Stress Reduction

Meditation is recommended for reducing anxiety. (Grade A)

Music therapy is recommended for reducing anxiety. (Grade B)

Stress management is recommended for reducing anxiety during treatment, but longer group programs are likely better than self-administered home programs or shorter programs. (Grade B)

Yoga is recommended for reducing anxiety. (Grade B)

Acupuncture, massage, and relaxation can be considered for reducing anxiety. (Grade C)

Chemotherapy-Induced Nausea and Vomiting

Acupressure can be considered as an addition to antiemetic drugs to control nausea and vomiting during chemotherapy. (Grade B)

Electroacupuncture can be considered as an addition to antiemetic drugs to control vomiting during chemotherapy. (Grade B)

Ginger and relaxation can be considered as additions to antiemetic drugs to control nausea and vomiting during chemotherapy. (Grade C)

Glutamine should not be recommended for improving nausea and vomiting during chemotherapy. (Grade D)

Depression and Mood Disturbance

Meditation, particularly mindfulness-based stress reduction, is recommended for treating mood disturbance and depressive symptoms. (Grade A)

Relaxation is recommended for improving mood disturbance and depressive symptoms. (Grade A)

Yoga is recommended for improving mood disturbance and depressive symptoms. (Grade B)

Massage is recommended for improving mood disturbance. (Grade B)

Music therapy is recommended for improving mood disturbance. (Grade B)

Acupuncture, healing touch, and stress management can be considered for improving mood disturbance and depressive symptoms. (Grade C)

Fatigue

Hypnosis and ginseng can be considered for improving fatigue during treatment. (Grade C)

Acupuncture and yoga can be considered for improving post-treatment fatigue. (Grade C)

Acetyl-l-carnitine and guarana should not be recommended for improving fatigue during treatment. (Grade D)

Lymphedema

Low-level laser therapy, manual lymphatic drainage, and compression bandaging can be considered for improving lymphedema. (Grade C)

Neuropathy

Acetyl-l-carnitine is not recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer due to potential harm. (Grade H)

Pain

Acupuncture, healing touch, hypnosis, and music therapy can be considered for the management of pain. (Grade C)

Quality of Life

Meditation is recommended for improving quality of life. (Grade A)

Yoga is recommended for improving quality of life. (Grade B)

Acupuncture, mistletoe, qigong, reflexology, and stress management can be considered for improving quality of life. (Grade C)

Sleep Disturbance

Gentle yoga can be considered for improving sleep. (Grade C)

Vasomotor/Hot Flashes

Acupuncture can be considered for improving hot flashes. (Grade C)

Soy is not recommended for hot flashes in patients with breast cancer due to lack of effect. (Grade D)

Integrative Therapies During and After Breast Cancer Treatment: ASCO Endorsement of the SIO Clinical Practice Guideline. Lyman GH, Greenlee H, Bohlke K, et al. J Clin Oncol. 2018;36:2647-2655

TECENTRIQ® and ABRAXANE® Significantly Prolonged Survival in Advanced Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and 40,920 women are expected to die from the disease. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway.

Previously published studies have shown that tumor-infiltrating lymphocytes were associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC. TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. Among patients with PD-L1–positive tumors, the addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. October 20, 2018. DOI: 10.1056/NEJMoa1809615

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer ASCO Clinical Practice Guideline Focused Update

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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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer.

ASCO published an adaptation of the Cancer Care Ontario guideline, on optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for HER2 (Human Epidermal Growth Factor receptor 2) positive breast cancers, in 2016. The recent publication of phase III studies relevant to the clinical care of breast cancer patients prompted the ASCO Update Steering Group of the original Expert Panel, to provide a focused update of the 2016 guideline. With the exception of this focused update, the remaining recommendations from the 2016 ASCO guideline are unchanged.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update

Questions Addressed in Focused Update

1) Should adjuvant Capecitabine be given following completion of standard preoperative Anthracycline- and Taxane-based combination chemotherapy in patients with early-stage HER2-negative breast cancer with residual invasive disease at surgery?

2) Should 1 year of adjuvant Pertuzumab be added to Trastuzumab-based combination chemotherapy in patients with early stage HER2-positive breast cancer?

3) Should Neratinib be offered as extended adjuvant therapy for patients after combination chemotherapy and Trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer?

Target Population

Patients who are being considered for, or who are receiving, systemic therapy following definitive surgery for early-stage invasive breast cancer, defined largely as invasive cancer anatomic Stages I to IIIC

Target Audience

Medical oncologists, Pathologists, Surgeons, Oncology nurses, Patients, and Caregivers.

Focused Update Recommendations

Patients with early-stage HER2-negative breast cancer with pathologic invasive residual disease at surgery following standard Anthracycline and Taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant Capecitabine (XELODA®).

Qualifying statements: If clinicians decide to use Capecitabine, then the Expert Panel preferentially supports the use of adjuvant Capecitabine in the subgroup of patients with Hormone Receptor negative, HER2-negative disease. The Capecitabine dosage used in the CREATE-X study (1,250 mg/m2 PO twice daily) is associated with higher toxicity in patients 65 years or older.

Clinicians may add 1 year of adjuvant Pertuzumab (PERJETA® ) to Trastuzumab (HERCEPTIN®)-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer.

Qualifying statements: The Expert Panel preferentially supports Pertuzumab in patients with node-positive, HER2-positive breast cancer in view of the clinically insignificant absolute benefit observed among node-negative patients. After a median follow up of 3.8 years, Pertuzumab offered a modest Disease Free Survival (DFS) benefit. The first planned interim analysis did not show an Overall Survival (OS) benefit in the trial population. There are no data to guide the duration of Pertuzumab in patients who received neoadjuvant Pertuzumab and achieved a pathologic Complete Response.

Clinicians may use extended adjuvant therapy with Neratinib (NERLYNX®) to follow Trastuzumab in patients with early stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea and diarrhea prophylaxis must be used.

Qualifying statements: The Expert Panel preferentially favors use of Neratinib in patients with HER2-positive, Hormone Receptor positive, and node-positive disease. At a median follow-up of 5.2 years, no OS benefit has been observed. Patients who began Neratinib within 1 year of Trastuzumab completion appeared to derive the greatest benefit. There are no data on the added benefit of Neratinib in patients who also received Pertuzumab in the neoadjuvant or adjuvant setting.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update. Denduluri N, Chavez-MacGregor M, Telli ML, et al. J Clin Oncol. 2018;36:2433-2443.

HER2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

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HER2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update
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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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. Accurate determination of HER2 status of the tumor is therefore essential for patients with invasive breast cancer, to ensure that those most likely to benefit are offered a HER2-targeted therapy and those who are unlikely to benefit can avoid toxicities as well as financial burden associated with those drugs.
Laboratory testing for HER2 status in patients with breast cancer in the US is performed according to guidelines developed by an Expert panel of members of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The ASCO/CAP guidelines were first published in 2007 and were updated in 2013. The Expert panel in 2018 developed and issued a focused update of the clinical practice guideline on HER2 testing in breast cancer. This new information made available since the previous update in 2013 addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. There are currently two approved methods for determining HER2 status in breast cancer: ImmunoHistoChemistry (IHC) and In Situ Hybridization (ISH). This new guideline enables the Health Care Provider, how to best evaluate some of the less common patterns in HER2 results emerging from ISH. 
Guideline Questions
1) What is the most appropriate definition for ImmunoHistoChemistry (IHC) 2+ (IHC equivocal)?
2) Must Human Epidermal growth factor Receptor 2 (HER2) testing be repeated on a surgical specimen if the initially tested core biopsy is negative?
3) What is the optimal algorithm for less common patterns observed when performing dual-probe In Situ Hybridization (ISH) HER2 testing in breast cancer?
Updated Recommendations
1) Immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in more than 10% of tumor cells.
2) If the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not “must”) be ordered on the excision specimen based on some criteria (such as tumor grade 3).
3)The HER2 testing algorithm now includes more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/Chromosome Enumeration Probe 17 [CEP17] ratio of 2.0 or more; average HER2 copy number less than 4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 6.0 or more signals per cell), and ISH group 4 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 4.0 or more and less than 6.0 signals per cell). These cases, described as ISH groups 2-4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC (ImmunoHistoChemistry) test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.
4)The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. 
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Wolff AC, Hammond EH, Allison KH, et al. J Clin Oncol 2018; 36:2105-2122.

HER2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

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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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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. Accurate determination of HER2 status of the tumor is therefore essential for patients with invasive breast cancer, to ensure that those most likely to benefit are offered a HER2-targeted therapy and those who are unlikely to benefit can avoid toxicities as well as financial burden associated with those drugs.

Laboratory testing for HER2 status in patients with breast cancer in the US is performed according to guidelines developed by an Expert panel of members of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The ASCO/CAP guidelines were first published in 2007 and were updated in 2013. The Expert panel in 2018 developed and issued a focused update of the clinical practice guideline on HER2 testing in breast cancer. This new information made available since the previous update in 2013 addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. There are currently two approved methods for determining HER2 status in breast cancer: ImmunoHistoChemistry (IHC) and In Situ Hybridization (ISH). This new guideline enables the Health Care Provider, how to best evaluate some of the less common patterns in HER2 results emerging from ISH.

Guideline Questions

1) What is the most appropriate definition for ImmunoHistoChemistry (IHC) 2+ (IHC equivocal)?

2) Must Human Epidermal growth factor Receptor 2 (HER2) testing be repeated on a surgical specimen if the initially tested core biopsy is negative?

3) What is the optimal algorithm for less common patterns observed when performing dual-probe In Situ Hybridization (ISH) HER2 testing in breast cancer?

Updated Recommendations

1) Immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in more than 10% of tumor cells.

2) If the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not “must”) be ordered on the excision specimen based on some criteria (such as tumor grade 3).

3)The HER2 testing algorithm now includes more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/Chromosome Enumeration Probe 17 [CEP17] ratio of 2.0 or more; average HER2 copy number less than 4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 6.0 or more signals per cell), and ISH group 4 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 4.0 or more and less than 6.0 signals per cell). These cases, described as ISH groups 2-4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC (ImmunoHistoChemistry) test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.

4)The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. 

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Wolff AC, Hammond EH, Allison KH, et al. J Clin Oncol 2018; 36:2105-2122.

KISQALI® plus FASLODEX® Improve Progression Free 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. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. 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. However, resistance to hormonal therapy occurs in a majority of the patients.

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 hormone receptor 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

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. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS compared with placebo plus endocrine therapy

MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival. Secondary end points included Overall Survival, Overall Response Rate, and Safety. The median time from randomization to data cutoff was 20.4 months.

Among all randomized patients, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The PFS benefit was consistent among the 367 patients who were treatment-naïve (HR=0.57) and 345 patients had received up to one line of prior endocrine therapy for advanced disease (HR=0.56). In the subgroup of patients taking KISQALI® plus FASLODEX® as first-line treatment, the median PFS was not reached and 70% were estimated to remain Progression Free at median follow up of 16.5 months. Among those patients with measurable disease at baseline, the Overall Response Rate was 40.9% for the KISQALI® plus FASLODEX® arm versus 28.7% for FASLODEX® plus placebo group (P=0.003). At first interim analysis, the Overall Survival data were immature. The most common grade 3/4 Adverse Events in patients receiving KISQALI® plus FASLODEX® compared to FASLODEX® alone were neutropenia (53.4% versus 0%) and leukopenia (14.1% versus 0%).

It was concluded that KISQALI® plus FASLODEX® might represent a new, first or second-line treatment option for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced breast cancer. MONALEESA-3 is the only randomized Phase III trial to study a CDK4/6 inhibitor plus FASLODEX® in the first-line setting, with demonstrable efficacy in patients with de novo advanced breast cancer and those who had not received adjuvant therapy in more than a year. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2 –) advanced breast cancer (ABC): Results from MONALEESA-3. Slamon DJ, Neven P, Chia SKL, et al. J Clin Oncol. 2018: 36, (suppl; abstr 1000).

Six Months Adjuvant HERCEPTIN® Safer and Efficacious in Early Stage HER2+ 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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 chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage breast cancer. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.HER2-Directed-Therapy

PERSEPHONE is a randomized, phase III, noninferiority trial in which a 6-month course of adjuvant HERCEPTIN® was compared with the standard 12-month course, among patients with HER2-positive early breast cancer. This study was conducted based on the hypothesis that shorter course of treatment with HERCEPTIN® could reduce cardiotoxicities as well as cost without compromising efficacy. This trial randomized 4089 patients across 152 sites in a 1:1 ratio to receive HERCEPTIN® for 6 months (N=2044) or 12 months (N=2045). In this trial, 69% of patients had ER-positive tumors, 41% received Anthracycline-based chemotherapy, 49% received Anthracycline and Taxane-based chemotherapy, 10% received Taxane-based chemotherapy, 85% received adjuvant chemotherapy, and sequential HERCEPTIN® was administered in 54% of patients. This study also included assessment of Left Ventricular Ejection Fraction (LVEF) every 3 months until month 12, as well as continued Quality of Life and health economic assessments at months 18 and 24. The Primary endpoint was Disease Free Survival (DFS) from the time of diagnosis.

At a median follow-up period of 5 years, the 4-year DFS rate was identical in both treatment groups. DFS was 89.8% with 12 months of HERCEPTIN® compared with 89.4% with the 6-month course, which met the criteria for noninferiority (P=0.01). Further, only 4% of the patients enrolled in the 6-month HERCEPTIN® group discontinued HERCEPTIN® treatment due to cardiotoxicities compared with 8% in the 12-month group (P<0.0001), suggesting that the number of patients stopping treatment due to cardiac toxicities was cut in half with the shorter duration of treatment with HERCEPTIN®. Patients receiving shorter course of HERCEPTIN® also had a more rapid recovery of their cardiac LVEF following treatment, compared with the standard of care group (P=0.02).

It was concluded from this largest, reduced duration, noninferiority trial that a shorter 6-month course of adjuvant HERCEPTIN® was noninferior for Disease Free Survival, compared with the standard 12-month schedule, among patients with HER2-positive early breast cancer, with an additional benefit of reduction in cardiac toxicities, as well as cost both to the patients and healthcare systems. Overall Survival data was not available at the time of this analysis. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. Earl HM, Hiller L, Vallier A-L, et al. J Clin Oncol 36, 2018 (suppl; abstr 506)