Tag: Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy which is the cornerstone of their 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. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

Upon development of metastatic disease, a subgroup of these patients, develop resistance to endocrine therapy. The most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting are the ESR1 mutations. These mutations promote ligand independent estrogen receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315) ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER positive, HER negative advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% vs 11%).

Droplet digital Polymerase Chain Reaction (ddPCR) is a highly sensitive and specific technique and can detect ESR1 mutations in the plasma. Retrospective studies have shown that ESR1 mutations detected in plasma cfDNA (cell free DNA) by ddPCR were associated with a lack of response to subsequent AI therapy. The authors in this publication used baseline plasma samples and assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials, the SoFEA trial and PALOMA-3 trial, which are representative of the current standard of care for ER positive advanced breast cancer.

In the SoFEA trial (Study of Faslodex With or Without Concomitant Arimidex), AROMASIN® (Exemestane), a steroidal AI, was compared with FASLODEX® (Fulvestrant)-containing regimens, in patients with prior sensitivity to nonsteroidal AIs (Letrozole and Anastrozole). In the PALOMA3 trial (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, FASLODEX® plus placebo was compared with FASLODEX® plus IBRANCE® (Palbociclib), in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital Polymerase Chain Reaction. (Multiplex PCR amplifies several different DNA sequences simultaneously and more information can be obtained from a single test run).

In the SoFEA trial, ESR1 mutations were found in 39.1% of patients of whom 49.1% were polyclonal. Polyclonal ESR1 mutations suggest that biopsy from a single metastatic site would fail to show capture these mutations. Patients with ESR1 mutations on FASLODEX® had improved Progression Free Survival (PFS) compared with AROMASIN® (HR=0.52; P=0.02). Patients with wild-type ESR1 had similar PFS after receiving either treatment (HR=1.07; P=0 .77). Ability to detect these mutations was not impacted by delays in processing of archival plasma. In the PALOMA3 trial, ESR1 mutations were found in the plasma of 25.3% of patients of whom 28.6% were polyclonal ESR1 mutations. The combination of FASLODEX® plus IBRANCE® improved PFS compared with FASLODEX® plus placebo in both ESR1 mutant (HR=0.43; P=0.002) and ESR1 wild-type patients (HR=0.49; P<0.001).

The authors concluded that plasma analysis for ESR1 mutations after progression on prior AI therapy may help direct choice of further endocrine-based therapy. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer. Fribbens C, O’Leary B, Kilburn L, et al. J Clin Oncol. 2016;34:2961-2968

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 life time. 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. The ASCO Clinical Practice Guidelines Committee endorsed a set of Cancer Care Ontario guideline recommendations that addressed the role of a range of patient and disease characteristics, in selecting adjuvant therapy for women with early-stage breast cancer. This guideline does not address the selection of optimal adjuvant chemotherapy regimens.

Guideline Question: Which patient and disease factors should be considered in selecting adjuvant therapy for women with early-stage breast cancer?

Target Population: Female patients who are being considered for, or who are receiving systemic therapy for early-stage invasive breast cancer (Stages I–IIA, T1N0–1, T2N0).

RECOMMENDATIONS

–Decisions regarding adjuvant therapy should be based on relevant (either prognostic or predictive) information and consideration given to-

1) Lymph node status, T stage, Estrogen Receptor status, Progesterone Receptor status, HER2 status, tumor grade, and presence of tumor lymphovascular invasion.

2) Risk-stratification tools including Oncotype DX score (for hormone receptor-positive, N0 or N1mic or isolated tumor cell, and HER2-negative cancers) and Adjuvant! Online.

3) Patient age, menopausal status, and medical comorbidities.

–For patients in whom chemotherapy would likely be tolerated and for whom chemotherapy is acceptable, adjuvant chemotherapy should be considered if the following characteristics are present:

1) Lymph node-positive tumor (at least one node with macrometastatic deposit > 2 mm)

2) Estrogen receptor-negative tumor (> 5 mm)

3) HER2-positive tumor

4) High-risk node-negative tumors (> 5 mm) and another high-risk feature

5) Adjuvant! Online 10-year risk of death from breast cancer > 10%.

–Patients with node-negative early stage breast cancer with high risk features who should be considered candidates for chemotherapy include

1) Tumors > 5 mm

2) Grade III histology

3) Triple negative tumors

4) Lymphovascular invasion

5) Oncotype DX recurrence score associated with an estimated distant relapse risk ≥ 15% at 10 years

6) HER2-positive tumors

(The ASCO panel suggested an estimated distant relapse risk > 20% in this setting).

–Patients with tumor size < 5 mm, node-negative tumors, and no other high-risk features, may not benefit from adjuvant chemotherapy.

–Adjuvant chemotherapy may not be required in patients with HER2-negative, strongly ER-positive, and PR-positive breast cancer and any of the following additional characteristics: positive nodes with micrometastasis only (< 2 mm), or Tumor size < 5 mm, or Oncotype DX recurrence score with an estimated distant relapse risk < 15% at 10 years. (The ASCO panel suggested an estimated distant relapse risk < 10% at 10 years in this setting)

ASCO Panel Discussion Points

Areas that warrant further consideration include-

1) Tumor histology and adjuvant therapy recommendations

2) Risk-stratification tools and proposed Oncotype DX recurrence score thresholds to guide decisions about chemotherapy

3) Patient factors in decision-making.

The panel noted that some uncommon breast cancer subtypes (eg, tubular, mucinous) may have a favorable prognosis and that such histologic information may be relevant for making decisions regarding adjuvant chemotherapy. Additionally, factors such as Grade III disease and lymphovascular invasion generally should not be used in isolation in decision-making but considered within the overall clinical context.

Role of patient and disease factors in adjuvant systemic therapy decision making for early-stage, operable breast cancer: Henry NL, Somerfield MR, Abramson VG, et al. American Society of Clinical Oncology endorsement of Cancer Care Ontario guideline recommendations. J Clin Oncol 34:2303-2311, 2016

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. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% 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 cancels it 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. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. The FDA in February 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. In a phase II study, a combination of IBRANCE® plus FEMARA® showed improved Progression Free Survival compared with FEMARA® alone, in the initial treatment of postmenopausal women with Estrogen-Receptor (ER) positive, HER2 negative advanced breast cancer. Based on this encouraging data, a phase III study was conducted, to confirm the efficacy and safety of IBRANCE® plus FEMARA® for this patient group.

In this double blind study (PALOMA-2), 666 postmenopausal women with ER positive, HER2 negative breast cancer, who had no prior therapy for advanced disease, were randomly assigned, in a 2:1 ratio to receive IBRANCE® plus FEMARA® (N=444) or placebo plus FEMARA® (N=222). IBRANCE® was administered at 125 mg PO daily, 3 weeks on and 1 week off, every 4 weeks and all patients received FEMARA® 2.5 mg PO daily . The median age was 62 years, 48% had visceral disease and 63% had prior systemic therapy for breast cancer. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate, Clinical Benefit Response and safety.

The median PFS was 24.8 months in the IBRANCE® plus FEMARA® group compared with 14.5 months in the placebo plus FEMARA® group (HR=0.58; P<0.001). This benefit was seen across all patient subgroups. The Objective Response Rate was 42% with the IBRANCE® plus FEMARA® combination and 35% with the placebo plus FEMARA® combination. The Clinical Benefit Response (complete response, partial response or stable disease for 24 weeks or more) was 84% in the IBRANCE® plus FEMARA® group and 71% in the placebo plus FEMARA® group (P<0.001). The most common grade 3 or 4 adverse events were neutropenia noted in 66% of the patients in the IBRANCE® group versus 1.4% in the placebo plus FEMARA® group. Approximately 10% of the patients in the IBRANCE® group permanently discontinued study treatment due to toxicities and 6% did so in the placebo plus FEMARA® group.

The authors concluded that a combination of IBRANCE® and FEMARA® significantly prolonged Progression Free Survival compared with FEMARA® alone, among patients with previously untreated ER-positive, HER2 negative advanced breast cancer and this combination should be the new standard of care for this patient group. Palbociclib and Letrozole in Advanced Breast Cancer. Finn RS, Martin M, Rugo HS, et al. N Engl J Med 2016; 375:1925-1936

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 update of the American Society of Clinical Oncology guideline concerning use of PostMastectomy RadioTherapy (PMRT) published in 2001, was developed by an expert panel following review of relevant literature published between January 2001 and July 2015 and further included a meta-analysis of 22 clinical trials published in 2014. Even though the use of PMRT has been widely accepted for patients with four or more positive lymph nodes, the role of PMRT for those with one to three positive nodes still remains controversial. This update addresses the issues at large and provides guidelines to help Health Care Providers and patients make informed decisions.

Clinical Question 1

Is PMRT indicated in patients with T1-2 tumors with one to three positive axillary lymph nodes who undergo Axillary Lymph Node Dissection (ALND)?

Recommendation 1a: The panel unanimously agreed that the available evidence shows that PMRT reduces the risks of locoregional failure, any recurrence, and breast cancer mortality for patients with T1-2 breast cancer and one to three positive lymph nodes. However, one has to weigh the risk and benefit with PMRT and individualize therapy. Patients with low tumor burden, favorable tumor characteristics, comorbidities, or coexisting conditions and limited life expectancy, may not be appropriate candidates for PMRT, as its potential toxicities outweigh the absolute benefit of PMRT.

Recommendation 1b: The decision to use PMRT should be made in a multidisciplinary fashion through discussion among providers from all treating disciplines, early in a patient’s treatment course, soon after surgery or before or soon after the initiation of systemic therapy.

Recommendation 1c: Decision making must fully involve the patients, so that they are able to weigh the risk/benefits of PMRT, with the best information provided by the treating Health Care Provider.

Clinical Question 2

Is PMRT indicated in patients with T1-2 tumors and a positive Sentinel Node Biopsy (SNB) who do not undergo completion ALND?

Recommendation: Patients with T1-2 tumors with positive sentinel lymph node biopsy, who choose not to have Axillary Lymph Node Disection, should receive PMRT only if there is already sufficient information to justify its use, without needing to know that additional axillary nodes are involved. SNB is generally performed at the time of mastectomy for this patient group, with omission of ALND if the nodes are negative. If the sentinel nodes are positive, ALND is performed. There is increasing controversy about whether ALND is always necessary, if there is limited disease in the affected sentinel nodes. This practice is based on extrapolation of data from randomized trials of patients treated exclusively or predominantly with breast-conserving surgery and whole-breast irradiation or breast plus axillary irradiation.

Clinical Question 3

Is PMRT indicated in patients presenting with clinical stage I or II cancers who have received NeoAdjuvant Systemic Therapy (NAST)?

Recommendation: Patients with axillary nodal involvement that persists after NAST, such as less than a complete pathologic response, should receive PMRT. Observational data suggest a low risk of locoregional recurrence for patients who have clinically negative nodes and receive NAST or who have a complete pathologic response in the lymph nodes with NAST.

Clinical Question 4

Should Regional Nodal Irradiation (RNI) include both the Internal Mammary (IMNs) and supraclavicular-axillary apical nodes when PMRT is used in patients with T1-2 tumors with one to three positive axillary nodes?

Recommendation: Radiation Therapy should generally be administered to both the IMNs and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast, when PMRT is used for patients with positive axillary lymph nodes.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update. Recht A, Comen EA, Fine RE, et al. Published online before print September 19, 2016, doi:10.1200/JCO.2016.69.1188

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. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. 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. 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.

Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. The FDA granted breakthrough designation for Abemaciclib based on a phase I trial in which this agent demonstrated significant single agent activity in refractory Hormone Receptor (HR) positive metastatic breast cancer. MONARCH 1 is a single arm phase II study which evaluated the single-agent activity of Abemaciclib in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer. This trial included 132 patients with HR-positive, HER2-negative metastatic breast cancer, whose disease progressed on or after endocrine therapy and chemotherapy. Patients had received a median of 3 lines of prior therapy for advanced disease and this included a median of 2 lines of chemotherapy. Approximately 50% of the patients had received FASLODEX® (Fulvestrant), 70% of patients had received Taxane based chemotherapy and 55 % of patients had received XELODA® (Capecitabine), in the metastatic setting. Abemaciclib was administered at 200 mg PO daily on a continuous schedule every 12 hours until disease progression. The median age was 58 yrs, 90% of the patients had visceral disease and 85% had at least 2 sites of metastatic disease. The primary endpoint was Objective Response Rate (ORR) and secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Clinical Benefit Rate (Complete Response plus Partial Response plus Stable Disease) and safety.

An interim analysis was performed at 8 months by when 35.6% of patients had received at least 8 cycles of Abemaciclib. The ORR was 17.4%, the Clinical Benefit Rate lasting for 6 months or more was 42.4%. The median time to response was 3.7 months and the median Duration of Response was 8.6 months. The median PFS was 5.7 months. The most common adverse events were diarrhea, fatigue, nausea, decreased appetite, abdominal pain and treatment discontinuation rate was infrequent at 6.8%.

It was concluded that CDK4 and CDK6 inhibitor, Abemaciclib, has significant antitumor activity in patients with refractory, HR-positive, HER2-negative metastatic breast cancer, for whom chemotherapy is the only option. Studies are underway combining Abemaciclib with FASLODEX®, for postmenopausal patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer who had progressed on 1 prior endocrine therapy (MONARCH-2 trial), as well as combining Abemaciclib with a nonsteroidal Aromatase Inhibitor in an earlier setting (MONARCH-3 trial), for patients with HR-positive, HER2-negative, locoregionally recurrent or metastatic breast cancer. MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Dickler MN, Tolaney SM, Rugo HS, et al. J Clin Oncol 34, 2016 (suppl; abstr 510)

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 life time. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 20-25% 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. HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. ASCO has established a process for adapting clinical practice guidelines of other organizations and this summary of the practice recommendations were adapted from the Cancer Care Ontario evidence based clinical practice guidelines, for the adjuvant treatment of HER2-positive early breast cancers.

Guideline Question: What is the optimal use of cytotoxic chemotherapy and Human Epidermal growth factor Receptor 2 (HER2) – directed therapy?

Target Population: Female patients who are being considered for, or who are receiving, systemic therapy after definitive surgery for early invasive breast cancer, defined largely as invasive cancer stages I to IIA (T1N0-1, T2N0).

RECOMMENDATIONS

Use of an Anthracycline-Taxane Regimen

1) An adjuvant chemotherapy regimen containing Anthracycline-Taxane is considered the optimal strategy for high risk patients, if they are able to tolerate this regimen.

2) For patients with high-risk disease who will not receive a Taxane, an optimal-dose Anthracycline three-drug regimen (cumulative dose of doxorubicin ≥ 240 mg/m2 or epirubicin ≥ 600 but no higher than 720 mg/m2) that contains Cyclophosphamide, is recommended. The cumulative dose of Doxorubicin in two-drug regimens should not exceed 240 mg/m2.

3) The addition of Gemcitabine or Capecitabine to an Anthracycline-Taxane regimen is not recommended for adjuvant chemotherapy.

Capecitabine in Patients 65 Years of Age and Older

In patients age 65 years or older, Capecitabine is not recommended as an adjuvant chemotherapy option in lieu of standard regimens like Doxorubicin plus Cyclophosphamide (AC) or Cyclophosphamide, Methotrexate, and Fluorouracil (CMF with oral cyclophosphamide).

CMF as an Alternative to AC

For patients in whom Anthracycline-Taxane is contraindicated, CMF (with oral cyclophosphamide) is an acceptable chemotherapy alternative to AC. The ASCO panel recommends classic CMF (oral cyclophosphamide days 1 to 14 with IV Methotrexate-Fluorouracil days 1 and 8, repeated every 28 days for six cycles) as the default adjuvant CMF regimen. However, the panel also recognizes IV CMF regimen given every 21 days.

Acceptable Adjuvant Chemotherapy Regimens for Patients with Higher-Risk Early-Stage Breast Cancer

1) FEC (Fluorouracil, Epirubicin, and Cyclophosphamide) × 3 → T (Docetaxel) × 3 (superior to FEC × 6)

2) AC × 4 → T × 4 (superior to AC × 4)

3) Docetaxel, Doxorubicin, and Cyclophosphamide × 6 (superior to Fluorouracil, Doxorubicin, and Cyclophosphamide × 6)

4) AC × 4 → paclitaxel (P) administered weekly

5) Dose-Dense AC → P (every 2 weeks)

Adjuvant Regimen When an Anthracycline Is Not Preferred

1) Docetaxel plus Cyclophosphamide (TC) × 4 is recommended as an alternative to AC × 4

2) Classic CMF with oral Cyclophosphamide for six cycles. The panel also recognizes IV CMF regimen given every 21 days.

Patient Selection and Adjuvant Trastuzumab Therapy

Only patients with HER2-positive breast cancer (overexpressed based on ImmunoHistoChemistry (IHC 3+) or amplified based on in situ hybridization [ISH ratio ≥ 2.0 or average HER2 copy number ≥ 6.0]), should be offered adjuvant Trastuzumab.

Trastuzumab Plus Chemotherapy

1) Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer greater than 1 cm in size.

2) Trastuzumab therapy can be considered in small, node-negative tumors (1 cm or less).

3) Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen.

4) The administration of Trastuzumab concurrently with the Anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity.

5) Trastuzumab should be preferentially administered concurrently (not sequentially) with a non-Anthracycline chemotherapy regimen.

6) Less cardiotoxicity is seen with TCH (Docetaxel, Carboplatin, and Trastuzumab) than with AC→TH (Doxorubicin and Cyclophosphamide→Docetaxel and Trastuzumab), and TCH is recommended for patients at higher risk for cardiotoxicity.

7) Even though there is no phase III evidence for the addition of Trastuzumab to some chemotherapy regimens, such as TC, those regimens might be in use and are reasonable options, particularly to mitigate cardiotoxicity in certain patients.

Duration of Trastuzumab Therapy and Cardiac Function Assessment

Patients should be offered 1 year total of adjuvant Trastuzumab, with regular assessments of cardiac function during that period.

Selection of Optimal Adjuvant Chemotherapy Regimens for Early Breast Cancer and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. Denduluri N, Somerfield MR, Eisen A, et al. J Clin Oncol 2016;34:2416-2427

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. Chemotherapy recommendations for early stage breast cancer are often made based on tumor size, grade, hormone receptor and HER-2 status, immunohistochemical markers such as Ki-67, nodal status, patients age, menopausal and performance status. Adjuvant! Online is one of the tools that incorporates these features and assists in treatment decision making. This tool however does not take into account individual tumor molecular signatures which can better predict clinical outcomes. MammaPrint® is a 70-gene signature assay approved by the FDA and is able to distinguish low risk and high risk tumors based on the risk of distant recurrence at 5 and 10 years. The authors in this study selected patients for adjuvant chemotherapy utilizing 70-gene signature assay in addition to standard clinicopathological criteria and prospectively reported 5-year outcomes in the treatment groups.

MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study is a international, prospective, randomized, phase III study which enrolled 6693 women with early-stage breast cancer and determined their genomic risk using the 70-gene signature assay (MammaPrint®) and their clinical risk using a modified version of Adjuvant! Online. Enrolled patients were divided into four groups based on their clinical and genomic risk: low clinical risk and low genomic risk (N=2745, 41%); high clinical risk and high genomic risk (N=1806, 27%), high clinical risk and low genomic risk (N=1550, 23.2%); low clinical risk and high genomic risk (N=592, 8.8%). Patients in the first 2 concordant groups were treated according to their risk category, ie. low-risk group did not receive adjuvant chemotherapy whereas adjuvant chemotherapy was added to endocrine therapy following surgery, in the high-risk patient group. Patients in the last 2 discordant groups were randomly assigned to receive adjuvant chemotherapy or no chemotherapy. The median age of the patients was 55 yrs, 79% of the patients had node-negative disease and 21% had 1-3 positive nodes. A total of 88% of the tumors expressed ER, PR, or both, and 9.5% were HER-2 positive.

The primary endpoint of this study was to show noninferiority against a predefined benchmark of a 5-year metastasis-free survival rate of 92%, in patients at high clinical risk, for whom a discordant low genomic risk led to the omission of otherwise standard adjuvant chemotherapy. It was noted that in this group of patients at high clinical risk and low genomic risk (N=1550) at 5 years, the rate of survival without distant metastasis was 94.7% among those not receiving chemotherapy, and this met the study criterion for noninferiority, with similar outcomes noted in all sub groups of patients.. The absolute difference in the survival rate between those who did not receive adjuvant chemotherapy and those who received chemotherapy was 1.5%, with the survival rate slightly higher in those who received adjuvant chemotherapy. The 5-year metastasis-free survival rate for women who were low risk by both genomic and clinical criteria and who did not receive adjuvant chemotherapy was 97.6%, compared with 90.6% for those women who were high risk by both criteria and who did receive adjuvant chemotherapy.

It was concluded that in patients with early stage breast cancer, who were considered to be at high clinical risk for recurrence, 70-gene signature assay was able to identify those with low genomic risk, who had marginal benefit with adjuvant chemotherapy. With treatment guidance using 70-gene signature assay, approximately 46% of early stage breast cancer patients with high clinical risk and low genomic risk might not require adjuvant chemotherapy. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. Cardoso F, van’t Veer LJ, Bogaerts J, et al. N Engl J Med 2016; 375:717-729