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 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. 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. The use of Aromatase Inhibitors (AIs) has been long associated with musculoskeletal symptoms, as well as accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD). Approximately 25% of the patients on AIs are non-compliant during the first year of therapy and this has been attributed to musculoskeletal symptoms. Increased risk of Carpal Tunnel Syndrome (CTS) has also been reported with AIs.

Carpal tunnel syndrome (CTS), also called median nerve compression, is the most common entrapment neuropathy and results from compression of the median nerve, as it runs from the forearm into the palm of the hand, through the carpal tunnel. The carpal tunnel is a narrow and rigid passage at the base of the hand and houses the median nerve and tendons. In most cases, CTS is due to a congenital predisposition, with the carpal tunnel being simply smaller in some individuals than others. Secondary CTS is caused by any condition that further narrows this osteofibrous passage such as arthritis, acromegaly and mechanical problems in the wrist joint or effects the contents of this passage such as tenosynovitis, synovial hypertrophy, hypothyroidism, fluid retention during pregnancy or menopause, or the development of a cyst or tumor in the passage. Bilateral oophorectomy and use of the combined oral contraceptive have also been identified as risk factors for CTS. Patients often experience nocturnal paraesthesias in median nerve distribution (thumb, index and middle fingers), such as burning sensation, tingling, or heaviness, with the pain radiating to the forearm or elbow. It has been postulated that estrogen has antinociceptive properties and estrogen deprivation with AIs decreases the threshold for pain stimuli. Estrogen deprivation may also impact the metabolism of transverse carpal ligament on which estrogen and progesterone receptors are expressed and lack of estrogen may additionally result in morphological changes in the contents of carpal tunnel including, thickening of the tendon sheaths and fluid accumulation. This may directly induce CTS.

To address the risk factors and incidence of CTS in women taking AIs, the authors conducted an exploratory analysis of the International Breast Cancer Intervention Study II, a double-blind randomized clinical trial, in which women at increased risk of breast cancer were randomly assigned to receive ARIMIDEX® or placebo for 5 years. In this study, a total of 3,864 women were randomly assigned to receive either ARIMIDEX® (N=1920) or placebo (N=1944). The median age was 60 years and majority of the women (69%) had a BMI of greater than 25 kg/m2.

After a median follow up of 6.4 years, 96 patients had symptoms of Carpal Tunnel Syndrome (CTS). Patients receiving ARIMIDEX® were more likely to have CTS related symptoms than those receiving placebo (3.4% versus 1.6%; P<0.001). Eight of the 10 participants reported as having severe CTS were taking ARIMIDEX® (P =0.08). Eighteen women (0.9%) in the ARIMIDEX® group required surgical intervention for CTS compared to six women (0.3%) in the placebo group and this was significantly different (P=0.018). Participants experiencing CTS symptoms did so early in the course of treatment and only 6 women discontinued the allocated treatment. In addition to taking AIs, high Body Mass Index and prior complaints of musculoskeletal symptoms, were the only other risk factors for developing CTS.

The authors concluded that the use of ARIMIDEX® was associated with a higher incidence of Carpal Tunnel Syndrome (CTS), although few participants required surgery. Given the association between CTS and other musculoskeletal symptoms induced by AIs (Aromatase Inhibitors), the authors suggested that these findings induced by AIs, may share the same pathobiology. Anastrozole-Induced Carpal Tunnel Syndrome: Results from the International Breast Cancer Intervention Study II Prevention Trial. Spagnolo F, Sestak I, Howell A, et al. J Clin Oncol 2016;34:139-143

SUMMARY: The FDA on February 19, 2016, approved IBRANCE® (Palbociclib) 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. 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 over 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. 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) and FEMARA® (Letrozole) are nonsteroidal Aromatase Inhibitors that binds reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. 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. 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. In an open-label, randomized, phase II study, which included treatment naïve postmenopausal women with ER-positive, HER2-negative, advanced breast cancer, IBRANCE® given along with Aromatase Inhibitor FEMARA® (Letrozole), significantly prolonged Progression Free Survival, Overall Response rate and median duration of response, compared to FEMARA® alone. Based on this data, the U. S. Food and Drug Administration in February 2015, granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA®, in this patient population. FASLODEX® (Fulvestrant) is a selective estrogen receptor down-regulator presently indicated for the treatment of hormone receptor positive metastatic breast cancer patients, with disease progression following antiestrogen therapy.

The PALOMA3 is double-blind, phase 3 study in which the efficacy and safety of the combination of IBRANCE® and FASLODEX® was evaluated, in premenopausal or postmenopausal women, with hormone receptor positive, HER-2 negative, advanced breast cancer, who had disease progression during prior endocrine therapy. Five hundred and twenty one (N=521) patients were randomly assigned in a 2:1 ratio to receive either FASLODEX® 500 mg IM on days 1 and 15 during cycle 1, of a 28 day cycle, and then on day 1 of each cycle thereafter, along with IBRANCE® 125 mg PO daily for 3 weeks, followed by 1 week off (N=347) or FASLODEX® and placebo (N=174). ZOLADEX® (Goserelin) was administered to premenopausal or perimenopausal patients for the duration of study treatment, starting at least 4 weeks before randomization and continuing every 28 days. The median age was 57 years. One previous line of chemotherapy for metastatic disease was allowed and 79% were post-menopausal, 60% had visceral disease and 75% of the patients had received a previous chemotherapy regimen.

The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rates, safety and tolerability. At the time of the preplanned interim analysis, the median Progression Free Survival was 9.2 months in the FASLODEX® / IBRANCE® group and 3.8 months in the FASLODEX® /placebo group (HR=0.42; P<0.001). This PFS benefit was observed across all prespecified patient subgroups, regardless of menopausal status. The most common grade 3 or 4 adverse events in the FASLODEX® / IBRANCE® group were neutropenia (62.0%, vs. 0.6%) and fatigue (2.0% vs. 1.2%). The incidence of febrile neutropenia was very rare (0.6%) and similar in both treatment groups. Treatment discontinuation rate due to adverse events was 2.6% in the IBRANCE® group and 1.7% in the placebo group.

The authors concluded that IBRANCE® in combination with FASLODEX® more than doubled the Progression Free Survival in advanced breast cancer patients, with hormone receptor positive and HER-2 negative disease, who had progressed on prior endocrine therapy. This study has reinforced the importance of CDK4 and CDK6, as key targets for hormone receptor positive breast cancer. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. Turner NC, Ro J, Andre F, et al. N Engl J Med 2015; 373:209-219

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 were 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). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. 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%. The National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with HERCEPTIN® for patients with small, HER positive, node-negative tumors, including those with T1bN0 tumors, even though there are little or no data supporting this recommendation, because these patients are generally not included in adjuvant therapy studies. Further, the chemotherapy regimens often recommended (ACTH, TCH) along with HERCEPTIN® are relatively toxic.

In a previously published study, it was noted that a less toxic regimen such as HERCEPTIN®, given along with weekly TAXOL® (Paclitaxel), had significant efficacy in patients with node negative patients with tumors measuring up to 3 cm in greatest dimension, decreasing the risk of recurrence in this patient group, most notable during the first three years after diagnosis. (Tolaney SM, Barry WT, Dang CT, et al. N Engl J Med 2015;372:134-141). Risk risk factors associated with HERCEPTIN® induced cardiotoxicity include, age over 50 years, borderline LVEF (Left Ventricular Ejection Fraction) before HERCEPTIN® treatment, history of cardiovascular disease, cardiovascular risk factors such as diabetes, dislipidemia or elevated body mass index (>30), sequence in which chemotherapy is administered and prior treatment with Anthracyclines (cumulative doses more than 300 mg/m2). However, unlike Anthracycline induced cardiotoxicity, HERCEPTIN® induced cardiotoxicity is reversible and there are no ultrastructural changes noted in cardiomyocytes in HERCEPTIN® induced cardiotoxicity.

This publication is a secondary analysis of the above mentioned previously published study and the authors here reported the cardiac safety data of a HERCEPIN® based nonanthracycline treatment, (TAXOL® with HERCEPTIN®), for patients with early-stage, node negative, HER2 positive breast cancer and the utility of monitoring LVEF in this patient group. This clinical trial enrolled 406 patients with node-negative, HER2 positive breast cancer 3 cm, or smaller with a baseline LVEF of 50% or greater. Treatment consisted of TAXOL® 80 mg/m2 IV weekly administered concurrently with HERCEPTIN® IV for 12 weeks, followed by HERCEPTIN® monotherapy for 39 weeks. HERCEPTIN® could be administered 2 mg/kg weekly or 6 mg/kg every 3 weeks during the monotherapy phase. Radiation and hormone therapy were administered as planned, following completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Median age was 55 years and 29% of the patients had hypertension, and 7% had diabetes. The median follow up was 4 years.

It was noted that a significant, asymptomatic LVEF decline was seen in 3.2% of the patients and 0.5% developed grade 3 Left Ventricular Systolic Dysfunction. The median LVEF at baseline was 65%, at 12 weeks was 64%, at 6 months was 64%; and at 1 year was 64%. The authors concluded that cardiotoxicity from a combination of TAXOL® and HERCEPTIN® is low and a baseline LVEF assessment may be adequate for the majority of patients although serial LVEF assessments could be considered for patients considered at a higher risk for cardiotoxicity. Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer. Dang C, Guo H, Najita J, et al. JAMA Oncol. 2016;2:29-36

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. The American Society of Clinical Oncology (ASCO) guidelines on the use of tumor markers in breast cancer are meant to provide evidence-based recommendations and guidance to practicing oncologists, on the appropriate use of breast tumor biomarker assays, for management of patients with metastatic breast cancer. These recommendations are for women with metastatic breast cancer being considered for systemic therapy or for changes in the drug or regimen they are receiving.

These guidelines were compiled after reviewing 17 clinical publications following an extensive literature search between 2006 and 2014. They included 11 studies that reported discordance in expression of hormone receptors or HER-2 between primary tumors and metastases, one randomized controlled study that addressed the use of a biomarker to decide whether to continue or change a treatment regimen and 5 prospective and retrospective studies that evaluated the clinical utility of biomarkers.

Should metastases be biopsied or otherwise sampled to test for changes from the primary tumor with respect to ER, PR, or HER2 status?

Patients with accessible, newly diagnosed metastases from primary breast cancer should be offered biopsy for confirmation of disease process and testing of ER, PR, and HER2 status. They should also be informed that if discordances are found, evidence is lacking to determine whether outcomes are better with treatment regimens based on receptor status in the metastases or the primary tumor. With discordance of results between primary and metastatic tissues, the Panel consensus is to preferentially use the ER, PR, and HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient's goals for care.

For women with metastatic breast cancer and with known ER, PR, and HER2 status, which additional tumor markers have demonstrated clinical utility to initiate systemic therapy or direct selection of a new systemic therapy regimen?

Decisions on initiating systemic therapy for metastatic breast cancer should be based on clinical evaluation, judgment, and patient preferences. There is no evidence at this time that initiating therapy solely on the basis of biomarker results beyond those of ER, PR, and HER2 improves health outcomes.

For women with metastatic breast cancer and with known ER, PR, and HER2 status, which additional tumor markers have demonstrated clinical utility to guide decisions on switching to a different drug or regimen or discontinuing treatment?

Recommendations for tissue biomarkers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient's goals for care. There is no evidence at this time that changing therapy based solely on biomarker results beyond ER, PR, and HER2 improves health outcomes, quality of life, or cost effectiveness.

Recommendations for circulating tumor markers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient's goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarker results improves health outcomes, quality of life, or cost effectiveness. CEA, CA 15-3, and CA 27-29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27-29 alone for monitoring response to treatment. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

For biomarkers shown to have clinical utility to guide decisions on systemic therapy for metastatic disease in questions 2 and 3, what are the appropriate assays, timing, and frequency of measurement?

Decisions for systemic therapy should be influenced by ER, PR, and HER2. ASCO recently updated the guideline addressing optimization of HER2 assays. To date, clinical utility has not been demonstrated for any additional biomarkers.

Poznak CV, Somerfield MR, Bast RC, et al. J Clin Oncol 2015;33:2695-2704

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 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. 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. Anastrozole,Letrozole and Exemestane are Aromatase Inhibitors that bind reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase inhibitors are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk. According to the WHO definitions, a healthy 30 year old adult (young adult) with the ideal Bone Mineral Density (BMD) is given a T-score of 0. A normal BMD is within 1 Standard Deviation-SD (+1 or −1) of the young adult mean. Osteopenia is between 1 and 2.5 SD below the young adult mean (−1 to −2.5 SD). Osteoporosis is 2.5 SD or more below the young adult mean (−2.5 SD or lower).

PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival by selectively targeting the RANK ligand. In this randomized, double-blind, phase III trial, the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® (Denosumab) on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 enrolled patients, 3420 patients were randomly assigned to receive PROLIA® 60 mg (N=1711) or placebo (N=1709) subcutaneously every 6 months. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA® . The primary endpoint was time from randomization to first clinical fracture.

Compared with placebo, PROLIA® significantly delayed time to first clinical fracture (HR=0.50; P<0•0001), with the PROLIA® group, half as likely to have a first clinical fracture as the placebo group. This benefit of lowering fracture risk was seen in subgroups of patients with BMD T-score of less than –1 as well as those with BMD T-score of -1 or greater. Further, patients in the PROLIA® group had improvements in BMD from baseline, of the lumbar spine, total hip, and femoral neck, compared to the placebo group, which showed worsening at all sites (P<0.0001). At 3 years, patients in the PROLIA® group had significantly lower risk of both new, or worsening vertebral fractures. No cases of osteonecrosis of the jaw bone were reported.

The authors concluded that PROLIA® administered in an adjuvant setting, significantly reduces the risk of fractures in postmenopausal women with breast cancer receiving Aromatase Inhibitors, without added toxicity. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Gnant M, Pfeiler G, Dubsky PC, et al. The Lancet 2015;386:433-443

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 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. Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides of loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density.

POEMS (Prevention of Early Menopause Study) is a randomized phase III trial designed to evaluate whether the addition of LHRH (Luteinizing Hormone-Releasing Hormone) analog Goserelin (ZOLADEX®), which suppresses the production of estrogens, to Cyclophosphamide based chemotherapy, would reduce POF in breast cancer patients, when compared to chemotherapy alone. Premenopausal patients less than 50 years of age, with hormone receptor negative (ER/PR negative ), Stage I-IIIA breast cancer, scheduled to receive chemotherapy, were randomly assigned to receive standard Cyclophosphamide based chemotherapy with or without monthly ZOLADEX® . Patients in the ZOLADEX® group received 3.6 mg SQ starting 1 week prior to the first dose of chemotherapy.

The primary endpoint was ovarian failure at two years (defined as amenorrhea for the prior 6 months AND post-menopausal FSH level). Other endpoints included pregnancy and survival rates. The median age of the patients was 38 years and median follow up was 4.1 years. Of the 218 evaluable patients, 135 premenopausal women were evaluable for the primary end point. POF rates were 22% in the chemotherapy alone group and 8% in the ZOLADEX® group (P=0.04). When the definition of POF was more liberal to include EITHER amenorrhea or elevated FSH but not both, POF rates were 45% in the chemotherapy alone group and 20% in the ZOLADEX® group (P=0.006). Among the 218 evaluable patients, more women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). Secondary outcomes also favored the ZOLADEX® group with a Disease free Survival (DFS) rate of 78% in the chemotherapy alone group compared with 89% in the ZOLADEX® group (P=0.04) and Overall Survival (OS) rate of 82% in the chemotherapy alone group compared with 92% in the ZOLADEX® group (P=0.05).

The authors concluded that the addition of ZOLADEX® to chemotherapy improved fertility prospects with a lower incidence of Premature Ovarian Failure and more pregnancies. Further, the improved Disease Free Survival and Overall Survival are important additional perks and prevention of Premature Ovarian Failure with ZOLADEX® may be a consideration not only in premenopausal breast cancer patients but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Goserelin for Ovarian Protection during Adjuvant Chemotherapy for Breast Cancer. Moore HC, Unger JM, Phillips K, et al. N Engl J Med 2015; 372:923-932

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Screening mammography complemented by breast self exam and clinical breast exam has resulted in early detection of breast cancer and successful outcomes. Even though mammography is a sensitive screening test, a small percentage of breast cancers may not show up on mammograms but may be palpable on examination by the patient or the clinician. Further, mammograms are less likely to find breast tumors in younger women with dense breast tissue. The following is a brief overview of the imaging techniques for breast cancer screening

Mammography

Mammography is performed by compressing the breast firmly between two plates and utilizes ionizing radiation to image breast tissue. During routine screening, breast tissue from the nipple to the pectoral muscle in the mediolateral oblique and craniocaudal views, is included. The radiation exposure is 4 to 24 mSv per standard two view screening examination. Two view screening is associated with a lower recall rate and lower interval cancer rates than are single-view exams. Breast Imaging Reporting and Data System (BI-RADS) categories are used for reporting mammographic results as follows:

0: Incomplete—needs additional image evaluation and/or prior mammograms for comparison.

1: Negative.

2: Benign.

3: Probably benign.

4: Suspicious.

5: Highly suggestive of malignancy.

6: Known biopsy—proven malignancy.

A digital mammogram is more expensive than screen-film mammography (SFM) and the data can be stored and shared. Compared with film mammography, sensitivity is higher for digital mammography, particularly in women younger than 50 years, but the specificity is either the same or lower than film mammography.

Computer-Aided Detection (CAD) systems increase detection of ductal carcinoma in situ (DCIS) by highlighting suspicious regions in the breast such as clustered microcalcifications and masses in mammograms. There is however no improvement in invasive cancer detection rate and there is an increase in recall rate.

Tomosynthesis

Tomosynthesis, or 3-Dimensional (3-D) mammography involves multiple short-exposure x-rays, from different angles and a three dimensional image is created for better visualization. A combination of 2-D and 3-D mammography has been reported to be more accurate than 2-D mammography alone, with the caveat that the radiation exposure to the patient is essentially doubled. Tomosynthesis in the diagnostic setting is at least as effective as spot compression views, for workup of non-calcified abnormalities, including asymmetries and distortions and may decrease the need for ultrasound testing.

Ultrasonography

Primarily utilized for the diagnostic evaluation of palpable or mammographically detected masses and distinguish solid tumors from cysts. It is a helpful adjunct modality in women with dense breast tissue. Images are created using high frequency sound waves with no radiation exposure. Evidence is lacking to support the use of ultrasound instead of mammography, at any age, in population based breast cancer screening.

Thermography

Thermography uses infrared imaging techniques and identifies temperature changes in the skin as an indicator of an underlying tumor. These changes are displayed in color patterns. The impact of thermography on breast cancer detection or mortality, has not been evaluated in randomized clinical trials and there appears to be no additional benefit for the use of thermography as an adjunct modality, for breast cancer screening.

Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) is more sensitive than mammography although the specificity of a breast MRI is lower, resulting in a higher rate of false-positive findings and potentially unnecessary biopsies. Microcalcifications in the breast can be missed by a breast MRI. The American Cancer Society (ACS) recommends an annual MRI as an adjunct to screening mammogram and clinical breast exam in certain groups with increased risk of breast cancer. They include individuals with deleterious genetic mutations such as BRCA1/2 mutation carriers, a strong family history of breast cancer, or several genetic syndromes such as Li-Fraumeni or Cowden disease. MRI may also be used to evaluate the integrity of silicone breast implants, assess palpable masses following surgery or radiation therapy, detect mammographically and sonographically occult breast cancer in patients with axillary nodal metastasis and preoperative planning for some patients with known breast cancer. Breast MRI is performed preferably between days 7-15 of menstrual cycle for premenopausal women, using a dedicated breast coil, with the ability to perform a biopsy under MRI guidance by experienced radiologists, during the same visit.

Molecular Breast Imaging

Molecular Breast Imaging (MBI) involves the injection of technetium-99m (Tc-99m) sestamibi, a radioactive substance, which then allows tumor visualization with a gamma camera. MBI along with mammography significantly increased the cancer detection rate in women with mammographically dense breasts, compared to mammography alone, in a recent study. This new technology is not yet widely available.

References: 1) American Cancer Society recommendations for early breast cancer detection in women without breast symptoms. http://www.cancer.org/cancer/breastcancer 2) National Cancer Institute: PDQ® Breast Cancer Screening. Bethesda, MD

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Approximately 5% to 10% of breast cancers are hereditary. The discovery of several new genetic mutations which can increase the risk of breast cancer, helped better understand inherited breast cancer susceptibility.

Genetic mutations in Breast cancer can be grouped into three categories:

1) High penetrance genes such as BRCA1 and BRCA2 gene mutations which account for 15–25% of the inherited breast cancers, TP53 gene mutations which cause the Li–Fraumeni syndrome, PTEN gene mutations which cause Cowden syndrome, STK11 gene mutations which cause Peutz–Jeghers syndrome and CDH1 gene mutations which cause hereditary diffuse gastric cancer. Under normal circumstances, the proteins produced from these genes act as tumor suppressors and are involved in repairing damaged DNA, which in turn helps to maintain the stability of a cell's genetic information. These gene mutations are rare and can result in a 10 fold increase in breast cancer risk.

2) Intermediate penetrance gene mutations increase the risk of breast cancer two to four fold. They include ATM, CHEK2, BRIP1, BARD1, and PALB2 gene mutations. Some of these genes provide instructions for making proteins that interact with the proteins produced from the BRCA1 or BRCA2 genes.

3) Low penetrance gene mutations such as FGFR2 gene mutations

MULTIGENE PANEL TESTING

Multigene panel testing can detect several more than the abnormal genes mentioned above and may also incidentally pick up an unexpected abnormal gene which may be associated with a low risk for cancer. This information can be emotionally stressful for patients, as there is little or no guidance regarding management. Further, multigene panel testing may find “Variants of Uncertain Significance” (VUS) which are genetic mutations that may or may not be linked to a disease. It is therefore imperative to counsel patients and families before and after genetic testing and adequate resources should be allocated to properly interpret the test results to these individuals.

WHICH GENES TO TEST

Actionable information from multigene panel testing can significantly benefit patients and family members. The testing panel should include BRCA1 and BRCA2 gene mutations as close to 10% of breast cancer patients with a strong family history who undergo multigene panel testing will have a deleterious mutation. Amongst them, about 6% will have BRCA1 or BRCA2 mutation and 4% will have gene mutations other than BRCA1and BRCA2. The panel testing should also include PALB2 gene mutations which carries a lifetime breast cancer risk of 33% to 58%, as well as CHEK2, ATM, and TP53 gene mutations for estrogen receptor positive breast cancer patients.

WHO SHOULD BE TESTED

1) A gene mutation linked to breast cancer is more likely if

2) Family is of Ashkenazi (Eastern European) Jewish descent.

3) Two or more first-degree (parent, sibling, or child) or second-degree (grandmother, granddaughter, aunt, niece, half-sibling) relatives were diagnosed with breast or ovarian cancer.

4) Breast cancer diagnosed before the age of 50 (premenopausal) in a close relative.

5) There is a family history of both breast and ovarian cancer.

6) Bilateral breast cancer was diagnosed in a close relative.

7) Male relatives were diagnosed with breast cancer.

8) Breast cancer is diagnosed in family and either male relatives on the same side of the family have had prostate cancer at a young age, or male or female relatives on the same side of the family have had gastrointestinal cancers, such as cancer of the pancreas, gall bladder or stomach.

Antoniou AC, Casadei S, Heikkinen T, et al. N Engl J Med 2014; 371:497-506.

National Comprehensive Cancer Network: Genetic/Familial High-Risk Assessment, Version 2.2015