Tag: Breast Cancer

Anthracycline Regimen Superior in High Risk Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The superiority of Anthracycline based chemotherapy regimens for the treatment of breast cancer was demonstrated in the mid 1980’s. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) overview analysis published in the Lancet in 1998 concluded that there was a 12% proportional reduction in the risk of recurrence and 11% proportional reduction in mortality with Anthracycline containing regimens versus non-Anthracycline containing chemotherapy regimens. There is however a small risk of cardiotoxicity even with cumulative doses of Doxorubicin of less than 550 mg/m2. Jones and colleagues in 2009 published the results of US Oncology Research Trial 9735 which compared TC with AC and concluded that TC is superior to AC chemotherapy regimen and would be a reasonable option for both younger and older patients requiring chemotherapy, who are hormone receptor positive or negative with either node negative disease or have 1-3 positive lymph nodes.

The ABC (Anthracyclines in early Breast Cancer) adjuvant phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49) done in sequence, were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles was non-inferior to combination regimens of Doxorubicin/Cyclophosphamide with Docetaxel or Paclitaxel (TaxAC), in patients with resected, high risk, HER2-negative breast cancer. The final analysis set from these collective trials known as ABC included 4130 patients, of whom 2078 patients were randomized to TC and 2052 patients to TaxAC. The treatment groups were well balanced. Sixty nine percent (69%) were hormone receptor positive, 41% were node negative and 51% had high grade tumors. The Primary Endpoint was invasive Disease Free Survival (iDFS) and the median follow up was 3.2 years.

At the time of pre-planned analysis with 399 invasive Disease Free Survival events, the 4 year DFS was significantly higher with TaxAC (90.7%) compared to 88.2% with TC (P=0.04). TaxAC provided little or no added benefit in hormone receptor positive and node negative patients. There was some benefit for patients with hormone receptor positive disease with 1-3 positive lymph nodes and those with hormone receptor negative disease with negative nodes. The most benefit was seen with TaxAC in patients with hormone receptor positive disease with 4 or more positive lymph nodes and in those with hormone receptor negative disease with positive nodes. The 4 year Overall Survival was comparable in both treatment groups although longer follow up is needed.

It can be concluded based on these findings that in early stage breast cancer, Anthracycline containing regimens are superior to non-Anthracycline regimens in patients with triple negative breast cancer and for those hormone receptor positive patients with 4 or more positive lymph nodes. There may be some benefit in select group of hormone receptor positive patients with 1-3 positive lymph nodes and in some patients with node negative, hormone receptor negative disease. Non-Anthracycline regimen such as TC is appropriate in node negative, hormone receptor positive patients. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Blum JL, Flynn PJ, Yothers G, et al. J Clin Oncol 34, 2016 (suppl; abstr 1000)

Late Breaking Abstract – ASCO 2016 Biosimilar of HERCEPTIN® Equally Effective and Safe

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SUMMARY: A Biosimilar product is a biological product that is approved based on its high similarity to an already approved biological product (also known as reference product). Biological products are made from living organisms including humans, animals and microorganisms such as bacteria or yeast and are manufactured through biotechnology, derived from natural sources or produced synthetically. Biological products have larger molecules with a complex structure than conventional drugs (also known as small molecule drugs). Unlike biological products, conventional drugs are made of pure chemical substances and their structures can be identified. A generic drug is a copy of brand name drug and has the same active ingredient and is the same as brand name drug in dosage form, safety and strength, route of administration, quality, performance characteristics and intended use. Therefore, brand name and the generic drugs are bioequivalent. The Affordable Care Act in 2010 created an abbreviated licensure pathway for biological products that are demonstrated to be “Biosimilar” to, or “interchangeable” with an FDA-licensed (FDA approved) biological product (reference product). The Biosimilar must show that it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. A Biosimilar product can only be approved by the FDA if it has the same mechanism of action, route of administration, dosage form and strength as the reference product, and only for the indications and conditions of use that have been approved for the reference product. Biosimilars are not as easy to manufacture as generics (copies of brand name drugs) because of the complexity of the structure of the biologic product and the process used to make a biologic product. The facilities where Biosimilars are manufactured must also meet the FDA’s standards.

Heritage is a double-blind, randomized phase III trial in which the efficacy and safety of Myl-1401O, a Biosimilar, was compared with HERCEPTIN®. The randomization included 500 patients treated at 95 sites worldwide, with centrally confirmed, measurable HER2 positive metastatic breast cancer, who had not received prior chemotherapy or HERCEPTIN® for their metastatic disease. Patients received either Myl-1401O or HERCEPTIN® along with TAXOTERE® (Docetaxel) or TAXOL® (Paclitaxel) administered every 3 weeks for a minimum of 8 cycles (24 weeks), with the antibody therapy continued, until disease progression. Both antibodies were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks. Approximately 44% of the enrolled patients had hormone receptor positive disease and 84% received TAXOTERE®. The final analysis included 458 patients of whom 230 were in the Myl-1401O group and 228 were in the HERCEPTIN® group. The Primary endpoint was Overall Response Rate (ORR) at 24 weeks and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) and Safety.

The ORR after 24 weeks of treatment was 69.6% for the Myl-1401O group and 64% for the HERCEPTIN® group and this was not statistically significant. The median PFS had not yet been reached. Safety data in both treatment groups were comparable and there was no significant change in cardiac function from baseline to Week 24 in either group. The dose-normalized maximum concentration and Area Under the Curve, were similar for both antibodies.

The authors concluded that this study is one of the first trials of Biosimilars in oncology to demonstrate similar results and they added that MYL-1401O is equivalent to HERCEPTIN®, when given in combination with a Taxane, as first line therapy, for patients with HER2 positive metastatic breast cancer. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. Rugo HS, Barve A, Waller CF, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA503)

Ovarian Suppression in Premenopausal Women with ER Positive Breast Cancer – ASCO Clinical Practice Guideline 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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 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. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues.

An Update Panel of the ASCO conducted a systematic review of randomized clinical trials investigating ovarian suppression and published this update. This information is an update of the ASCO adjuvant endocrine therapy guideline, regarding the risks and benefits of ovarian suppression in addition to standard adjuvant therapy, in premenopausal women with Estrogen Receptor positive breast cancer. The ASCO Update Panel addressed the following questions with regard to premenopausal women with stage I-III hormone receptor-positive Breast Cancer:

1) Should premenopausal women with ER positive tumors receive adjuvant ovarian suppression in addition to standard adjuvant therapy, and, if so, in which subsets of patients?

2) If ovarian suppression is recommended, should ovarian suppression be administered in combination with Tamoxifen or an Aromatase Inhibitor?

Recommendation 1

1.1 The panel recommends that higher risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not. (For women with higher risk cancers who receive chemotherapy but remain premenopausal, ovarian suppression added to Tamoxifen reduces the risk of breast cancer recurrence).

1.2 Women with stage II or III Breast Cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression in addition to endocrine therapy.

1.3 Women with stage I or II breast cancers at higher risk of recurrence, who might consider chemotherapy, may also be offered ovarian suppression in addition to endocrine therapy.

1.4 Women with stage I breast cancers not warranting chemotherapy should receive endocrine therapy but not ovarian suppression.

1.5 Women with node-negative cancers 1 cm or less (T1a, T1b) should receive endocrine therapy but not ovarian suppression.

Qualifying Statements

• The standard duration of ovarian suppression in the included trials was 5 years. The panel therefore supports ovarian suppression for 5 years as there is no comparative data available on alternative durations.

• To date, there is no adequate evidence for assessing the benefit of adjuvant ovarian suppression in women at sufficient risk to warrant chemotherapy compared with 10 years of Tamoxifen.

• There is no current role for ovarian suppression as adjuvant therapy in ER negative breast cancers.

• There are substantial adverse effects related to ovarian suppression. Clinicians and patients should take this into consideration when choosing ovarian suppression.

• The long-term effects of ovarian suppression on breast cancer risk and survival are not yet established.

Recommendation 2

Ovarian suppression may be administered with either Tamoxifen or an Aromatase Inhibitor.

Qualifying Statements

• Tamoxifen and Aromatase Inhibitor therapy differ in their side effect profiles, which may affect patient preferences.

• Clinicians should be alert to the possibility of incomplete ovarian suppression with Gonadotropin-Releasing Hormone agonist therapy and evaluate patients for whom there is concern about residual ovarian function.

Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 2016;34:1689-1701

IBRANCE® (Palbociclib)

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The FDA on February 19, 2016 approved IBRANCE® in combination with FASLODEX® (Fulvestrant) for the treatment of women with hormone receptor (HR) positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy. IBRANCE® capsules are a product of Pfizer, Inc.

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer – Part II

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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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. Developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies and prospective comparative observational studies published from 2006 through 2014, these recommendations are meant to provide guidance to the Health Care Provider, as appropriate treatment is considered for patients with newly diagnosed, early-stage invasive breast cancer.

Two important questions were addressed by these guidelines – The Part I edition last week (www.oncoprescribe.com) addressed the first clinical question. This week’s edition (Part II) addresses the second clinical question.

Clinical Question 2: For women with early-stage invasive breast cancer and with known estrogen receptor/progesterone receptor and HER2 status, which additional biomarkers have demonstrated clinical utility to guide the choice of specific drugs or regimens for adjuvant systemic therapy?

Tamoxifen

CYP2D6 polymorphisms should not be used to guide adjuvant endocrine therapy selection. The expression of p27 by IHC should not be used to guide adjuvant endocrine therapy selection.

Aromatase Inhibitors

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide adjuvant endocrine therapy.

Taxanes

Microtubule-associated protein Tau mRNA expression or mRNA expression by IHC should not be used to guide adjuvant chemotherapy selection. HER1/Epidermal Growth Factor Receptor expression by IHC should not be used to guide adjuvant chemotherapy selection.

Anthracyclines

TOP2A gene amplification or TOP2A protein expression by IHC should not be used to guide adjuvant chemotherapy selection. HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 should not be used to guide adjuvant chemotherapy selection.

Trastuzumab

If a patient has HER2 positive breast cancer, PTEN should not be used to guide adjuvant therapy selection. If a patient has HER2 positive breast cancer, soluble HER2 levels should not be used to guide the selection of the type of adjuvant therapy.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer Part 1

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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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies, published from 2006 through 2014. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Two important questions were addressed by these guidelines – This edition (Part 1) addresses the first Clinical Question

Clinical Question 1: For women with early-stage invasive breast cancer and with known Estrogen receptor/Progesterone receptor and HER2 status, which other biomarkers have demonstrated clinical utility to guide decisions on the need for adjuvant systemic therapy?

Oncotype DX

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, the Oncotype DX 21-gene recurrence score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node positive disease. It should not be used in patients with HER2 positive or triple negative disease.

PAM50 Risk of Recurrence Score

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the PAM50 Risk of Recurrence score may be used in conjunction with other clinicopathologic variables to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive breast cancer and those with triple-negative breast cancer to guide decisions on adjuvant systemic therapy.

EndoPredict

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, EndoPredict 12-gene risk score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple-negative disease.

Breast Cancer Index

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the Breast Cancer Index may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple negative breast cancer to guide decisions on adjuvant systemic therapy.

Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

MammaPrint

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the MammaPrint 70-gene assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive disease. It should not be used in patients with triple negative breast cancer.

Mammostrat

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the Mammostrat 5-protein assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Immunohistochemistry 4

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Immunohistochemistry 4 (IHC4) should not be used to guide decisions on adjuvant systemic chemotherapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Circulating Tumor Cells

The clinician should not use circulating tumor cells to guide decisions on adjuvant systemic therapy.

Tumor-Infiltrating Lymphocytes

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Tumor-Infiltrating Lymphocytes should not be used for decision making. It should not be used in patients with HER2 positive or triple negative breast cancer.

Protein Encoded by MKI67 Gene

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide choice on adjuvant chemotherapy.

Extended Endocrine Therapy

If a patient has ER/PR positive, HER2 negative (node-negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or IHC4) should not be used to guide decisions on extended endocrine therapy.

The Clinical Question 2 will be addressed in the eNL edition (Part 2) next week.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

Late Breaking Abstract – ASCO 2016 Extended Adjuvant AI Therapy Improves DFS in Postmenopausal Hormone Receptor Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 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. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Postmenopausal women with hormone receptor positive early breast cancer are often treated with 5 years of Aromatase Inhibitor (AI) therapy either as up-front treatment or after 2-5 years of Tamoxifen. The benefit of extending treatment with an AI to 10 years may further reduce the risk of breast cancer recurrence, but this benefit was not previously known.

The Canadian Cancer Trials Group MA.17R is a double blind, placebo controlled, phase III trial, which tested the benefit of extending AI treatment, using FEMARA®, for an additional 5 years. This study involved 1,918 postmenopausal women with early stage breast cancer and included three patient groups – one group had no prior treatment with adjuvant Tamoxifen whereas the other two groups had adjuvant Tamoxifen for some duration of time. All patients however had recently received 4.5 to 6 years of adjuvant AI therapy. These patients were then randomly assigned to receive either extended adjuvant treatment with FEMARA® or placebo for an additional five years. The primary endpoint was Disease Free Survival (DFS).

After a median follow up of 6.3 years, the 5 year DFS rate for the extended FEMARA® group was 95% compared with 91% for the placebo group (HR=0.66; P=0.01). The improvement in DFS was significant among patients with node-positive disease, but not for those with node-negative disease. There was no difference in the 5 year Overall Survival between the two groups – 93% with FEMARA® versus 94% with placebo (HR 0.97; P=NS). The annual incidence rate of contralateral breast cancer was however significantly better in the FEMARA® group at 0.21%, compared with 0.49% with placebo (HR=0.42; P=0.007). Patients receiving extended treatment with FEMARA® had more frequent adverse events such as bone pain, elevation of alkaline phosphatase, and elevation of alanine transaminase. There was also a greater incidence of osteoporosis with FEMARA® than with placebo (11% vs 6%; P<0.0001) and fracture risk was higher in the FEMARA® group (14%) compared with 9% in the placebo group (P=0.001).

The authors concluded that this is the first study to show added benefit of improved Disease Free Survival, by extending an adjuvant AI beyond 5 years to 10 years, when compared with 5 years of AI treatment as initial therapy or preceded by 2-5 years of Tamoxifen. A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. Goss PE, Ingle JN, Pritchard KI, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA1)

Adjuvant AROMASIN® Most Beneficial for Premenopausal Women with High Risk 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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 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. 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. Presently available therapies include Tamoxifen and other Selective Estrogen Receptor (ER) Modulators, which modulate ER alpha activity, Aromatase Inhibitors (AIs) and Ovarian ablation that decrease estrogen production and FASLODEX® (Fulvestrant) that down regulates Estrogen Receptor. Aromatase Inhibitors are often prescribed due to their superiority over Tamoxifen, for postmenopausal women with Hormone Receptor positive breast tumors, in adjuvant as well as metastatic settings. Aromatase Inhibitors by themselves however, are not effective in premenopausal women, as these individuals derive their estrogen mainly from ovaries and not extragonadal tissue.

The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) are two phase III randomized trials, conducted at the same time and included premenopausal women (average age was 43 years) with hormone receptor positive, early breast cancer. In the joint analysis of these two trials which included 4,891 women, the authors set out to answer 2 important questions – whether adjuvant AI treatment improves outcomes in this patient group, when their Ovarian Function is suppressed and whether there is any benefit with Ovarian Function suppression in premenopausal women suitable for adjuvant Tamoxifen. TEXT randomized patients within 3 months of surgery to 5 years of AROMASIN® (Exemestane) plus Ovarian Function Suppression (OFS) or 5 years of Tamoxifen plus OFS. The SOFT study randomized patients to 5 years of AROMASIN® plus OFS or 5 years of Tamoxifen plus OFS or 5 years of Tamoxifen alone. OFS choices included oophorectomy, ovarian irradiation or 5 years of TRELSTAR® (Triptorelin), a GnRH (Gonadotropin Releasing Hormone) agonist. The 5 year Disease Free Survival was 91.1% in the AROMASIN® plus OFS group and 87.3% in the Tamoxifen plus OFS group (HR=0.72, P<0.0002). Compared to patients receiving Tamoxifen plus OFS, AROMASIN® plus OFS reduced the relative risk of premenopausal women developing a subsequent invasive breast cancer by 28% and the relative risk of breast cancer recurrence by 34%.

The authors in this analysis examined the absolute treatment effect in the TEXT and SOFT trials across a continuum of recurrence risk, to help individualize decision making for endocrine therapy, in premenopausal women with Human Epidermal growth factor Receptor 2 (HER2) -negative disease. Incorporating age, nodal status, tumor size, grade, Ki-67 expression levels and hormone receptor status, a composite recurrence risk for each patient was determined, from a Cox model.

It was noted that patients in the SOFT trial who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year Breast Cancer-Free Interval with AROMASIN® plus OFS compared with Tamoxifen plus OFS or Tamoxifen alone, and this benefit was even higher, reaching 10% to 15% for the intermediate to high composite recurrence risk group of patients. Patients in the SOFT trial whose composite recurrence risk was low did not receive chemotherapy and did well with all endocrine therapies. For patients in the TEXT trial, the benefit of AROMASIN® plus OFS compared with Tamoxifen plus OFS was similar to the SOFT trial, with the 5-year Breast Cancer-Free Interval ranging from 5-15%. Again, patients not receiving chemotherapy and with lowest composite recurrence risk did well with both endocrine therapies.

The authors concluded that premenopausal women with hormone receptor-positive, HER2-negative disease, with high risk for recurrence based on clinicopathologic features, may experience a 10% to 15% improvement in the 5-year Breast Cancer-Free Interval with AROMASIN® plus OFS compared with Tamoxifen alone. Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women with Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer: TEXT and SOFT Trials.Regan MM, Francis PA, Pagani O, et al. Published online before print April 4, 2016, doi: 10.1200/JCO.2015.64.3171 JCO April 4, 2016 JCO643171

Five Year Follow up Data without Adjuvant Chemotherapy, Utilizing Oncotype DX 21-gene Recurrence Score Assay

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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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. 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 early stage, hormone receptor positive, HER negative breast cancer patients, are often made based on tumor size, grade, immunohistochemical markers such as Ki-67, nodal status and 21-gene Recurrence Score (RS) assay.

The West German Study Group (WSG) PlanB phase III trial, used Recurrence Score assay prospectively, to define a low risk subset of patients with node negative disease with high risk traditional parameters and patients with node positive disease (HR+, HER2 negative), who could be treated with adjuvant endocrine therapy alone, sparing chemotherapy. In this study, patients with a Recurrence Score of 11 or less were defined as having low risk for recurrence, even in those considered to have tumor with high risk features such as large tumor size, high tumor grade and lymph node involvement. Patients were considered to be at intermediate or high risk if they had a Recurrence Score of 12 or more and 25 or more, respectively. Gluz and colleagues had previously reported 3-year follow up results of a planned interim analysis of this study, and were able to show significant difference between tumor grade, Ki-67 and Oncotype DX Recurrence Score.

In this current analysis, the authors reported the 5-year Disease Free Survival (DFS) outcomes of this large prospective trial. This analysis included data from 3,198 patients with early stage hormone receptor positive or HER2 negative breast cancer. The median age was 56 years and 32.5% of the patients had grade 3 tumors and 41% of the patients had node positive disease. Patients with a Recurrence Score of 11 or less received hormonal therapy and adjuvant chemotherapy was omitted. The intermediate and high risk patients were randomized to receive six cycles of TAXOTERE® (Docetaxel)/CYTOXAN® (Cyclophosphamide) or four cycles of ELLENCE® (Epirubicin)/CYTOXAN® followed by four cycles of TAXOTERE®. The primary endpoint was Disease Free Survival (DFS) defined as invasive or noninvasive relapse.

It was noted that the 5-year DFS in the low risk group was 94%, 84% in the high risk group and 94% in the intermediate risk group (P<0.001). It should be noted that approximately 15% of the patients in the clinically determined intermediate or high risk group, with 0-3 lymph node involvement, fell in the low genomic risk group (Recurrence Score of 11 or less) and received hormonal therapy alone.

The authors concluded that West German Study Group (WSG) PlanB study is the first trial that has reported five year survival data using 21-gene Recurrence Score assay, which can identify patients with early breast cancer, who would benefit from hormonal therapy alone and could be spared chemotherapy. Based on these data, 21-gene Recurrence Score has stronger prognostic value compared to immunohistochemical studies such as Ki-67 and hormone-receptor expression and should therefore be routinely incorporated in clinical practice as a decision making tool for this patient population, in addition tumor size, grade and nodal status. Prospective WSG Phase III PlanB trial: Clinical outcome at 5 year follow up and impact of 21 Gene Recurrence Score result, central/local-pathological review of grade, ER, PR and Ki67 in HR+/HER2- high risk node-negative and –positive breast cancer. Gluz O, Nitz U, Christgen M, et al. Abstract 8LBA. Presented at: 10th European Breast Cancer Conference; March 9-11, 2016; Amsterdam.

Impact of Treatment Delay on Clinical Outcomes 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. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Even though majority of the patients start their adjuvant chemotherapy within 4-6 weeks following surgery, the impact of delay in the initiation of adjuvant therapy on outcomes, has remained unclear. Preclinical models have suggested that there is phase of increased angiogenesis and accelerated growth of micrometastases, as well as development of drug resistant clones, following removal of the primary tumor. Previously published data from a large meta-analysis had suggested that a four week delay in the initiation of adjuvant chemotherapy resulted in a 6% increase in the risk of death and an 8% increase in the risk of relapse. Nonetheless, over the past 2 decades, there has been increasing delay for both surgery and adjuvant chemotherapy treatment intervention, following diagnosis of breast cancer. These delays have been attributed to the increasing use of prognostic tools prior to treatment intervention, in order to optimize breast cancer care, germ-line genetic testing to plan appropriate surgical intervention, as well as patients seeking immediate reconstructive surgical options. Two studies addressed the impact of delay in treatment intervention following diagnosis of breast cancer, by investigating outcomes, in a very large group of patients with breast cancer.

In the study by Bleicher, et al., the relationship between the time from diagnosis to breast cancer surgery and survival was investigated, by collecting data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort had 94,544 patients 66 years or older, diagnosed between 1992 and 2009 and the NCDB cohort included 115,790 patients 18 years or older, diagnosed between 2003 and 2005. Patients included in this analysis underwent surgery as initial treatment and had a diagnosis of non-inflammatory, non-metastatic, invasive breast cancer. The primary outcome was Overall and Disease-Specific Survival, as a function of time between diagnosis and surgery, measured in 30 day increments. They noted that with each interval of treatment delay increase, Overall Survival was lower (HR=1.09; P<0.001 in the SEER-Medicare cohort and HR=1.10; P<0.001 in the NCDB cohort). This relationship was statistically significant only in stages I and II breast cancer. The authors in this study concluded that longer time to surgery is associated with lower Overall and Disease-Specific Survival.

Chavez-MacGregor et al. analyzed the outcomes of 24, 843 patients in the California Cancer Registry with stage I-III invasive breast cancer, diagnosed between January 2005 and December 2010, and treated with adjuvant chemotherapy. Time to chemotherapy was defined as the number of days between surgery and the first dose of chemotherapy, and delayed treatment was defined as 91 or more days from surgery to the first dose of adjuvant chemotherapy. Median age at the time of diagnosis was 53 years, and median time to adjuvant chemotherapy was 46 days. Patients were evaluated for Overall Survival and Breast Cancer-Specific Survival. They noted that patients receiving adjuvant chemotherapy 91 or more days following surgery experienced worse Overall Survival (HR=1.34) and worse Breast Cancer-Specific Survival (HR=1.27) compared with patients receiving adjuvant chemotherapy within 31 days from surgery and these adverse outcomes were even more so, among patients with triple negative breast cancer (HR=1.53). Factors associated with adjuvant therapy delays included, low socioeconomic status, breast reconstruction, non-private insurance, and Hispanic or African American ethnicity. The authors in this study concluded that delaying initiation of adjuvant chemotherapy 91 days or more, results in adverse outcomes and this may be even more detrimental, in patients with triple negative breast cancer.

These two studies strongly suggest that treatment delays should be avoided in patients with early stage breast cancer and if surgery is to be delayed, neoadjuvant treatment approach may be reasonable, to avoid adverse outcomes.

Time to Surgery and Breast Cancer Survival in the United States. Bleicher RJ, Ruth K, Sigurdson ER, et al. JAMA Oncol. 2016;2:330-339.

Delayed Initiation of Adjuvant Chemotherapy Among Patients With Breast Cancer. Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, et al. JAMA Oncol. 2016;2:322-329.