Tag: Breast Cancer

FDA Approves DigniCap Cooling System for Prevention of Chemotherapy Induced Alopecia

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SUMMARY: The FDA on December 8, 2015 allowed the marketing of the first cooling cap in the US, Dignitana DigniCap Cooling System, to reduce hair loss, in female breast cancer patients undergoing chemotherapy. Alopecia (hair loss) is a common side effect of several chemotherapeutic agents and can be emotionally traumatic. Even though temporary, minimizing or alleviating hair loss, can have a significant impact on patients psychological well being and willingness to pursue necessary treatment. Presently available non-FDA approved cooling devices include Penguin Cold Caps and Paxman Scalp Cooling System, although the later is not available in the US. One of the major concerns with cold caps use has been the risk for scalp metastasis due to decreased chemotherapy access to the scalp tissue from vasoconstriction associated with cooling devices. It is clear now that that the risk of metastases to the scalp is extremely rare and low (1.2%) and even lower as an initial event for advanced disease.

The Dignitana DigniCap computer-controlled cooling system pumps liquid coolant through a head-worn silicone cooling cap during chemotherapy treatment. This cooling cap is covered by an outer insulating cap which holds the cooling cap in place. The circulating coolant inside the cap gradually gets colder. The cold and near freezing temperature constricts the blood vessels in the scalp, which, in turn reduces chemotherapy access in the hair follicles, as well as metabolic activity of the hair follicle cells, thus slowing cell division. This combined action impairs the effect of chemotherapy on hair follicles and reduces chemotherapy induced hair loss.

The FDA approval was based on a multicenter prospective open-label, nonrandomized study in which the efficacy of the cooling system was studied in 122 women with Stage I and Stage II breast cancer who were receiving chemotherapy regimens associated with hair loss. The primary endpoint was patient self-assessment of hair loss using standardized photographs at three to six weeks after the last chemotherapy cycle. A score of 0-2 (50% or less hair loss) was defined as treatment success. Patients who chose not to undergo scalp cooling were enrolled in a control group. It was noted that more than 66 percent of patients treated with the DigniCap reported losing less than half their hair whereas 94% had more than 75% hair loss in the control group. The most common side effects with the scalp cooling system included cold-induced headaches and neck and shoulder discomfort, chills and pain associated with wearing the cooling cap for prolonged period of time.

The authors concluded that the DigniCap System is highly effective in reducing chemotherapy-induced alopecia and the FDA approval of this scientifically proven option will provide a major relief for cancer patients receiving chemotherapy. Clinical performance of the DigniCap system, a scalp hypothermia system, in preventing chemotherapy-induced alopecia. Rugo HS, Klein P, Melin SA, et al. J Clin Oncol 33, 2015 (suppl; abstr 9518)

Preserving Fertility with ZOLADEX® in 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, 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

Breast Cancer Screening Imaging Modalities – A Primer

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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, 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

Genetics of Breast Cancer – A Primer

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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, 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

Late Breaking Abstract – ASCO 2015 IBRANCE® More Than Doubles Progression Free Survival in Hormone Receptor Positive Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. 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 and 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 prevent 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 on February 3, 2015 granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA® (Letrozole) 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 33% of the patients had prior chemotherapy for advanced disease. 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=0.422; P<0.000001). This PFS benefit was observed across all prespecified patient subgroups, regardless of menopausal status. The most common adverse events in the IBRANCE® group were neutropenia (78.8% vs 3.5%) and fatigue (38.0% vs 26.7%). 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% 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. June 1, 2015DOI: 10.1056/NEJMoa1505270

Late Breaking Abstract – ASCO 2015 ARIMIDEX® may be a Better Treatment Option Compared to Tamoxifen in Postmenopausal Women with DCIS

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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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease.Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. 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 is a non-steroidal Aromatase Inhibitor that binds reversibly to the aromatase enzyme and inhibits the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase Inhibitors such as ARIMIDEX® have been proven to be superior to Tamoxifen, as adjuvant therapy, in postmenopausal patients with hormone receptor positive breast cancer. It was however not known whether ARIMIDEX® was superior to Tamoxifen in preventing the recurrence of breast cancer.

NSABP B-35 is a randomized phase III trial which compared ARIMIDEX® to Tamoxifen, in preventing the recurrence of breast cancer, in postmenopausal women with Ductal Carcinoma In Situ (DCIS), who underwent lumpectomy and radiation therapy. Of the 3,104 patients who were enrolled and randomized, 1552 patients received ARIMIDEX® 1 mg PO daily and 1552 patients received Tamoxifen 20 mg PO daily. Treatment was continued for 5 years. Enrolled patients had tumors with no invasive component, Estrogen or Progesterone Receptors were positive and margins of resection were clear. The primary endpoint was Breast Cancer-Free Interval (BCFI), defined as the time from randomization to any breast cancer event including local, regional, or distant recurrence or contralateral invasive cancer or DCIS. With a median follow up of 8.6 years, the 10 year Breast Cancer–Free Interval rates were 93.5% with ARIMIDEX® versus 89.2% with Tamoxifen, and this was statistically significant (HR=0.73, P=0.03). This benefit was more so in women less than 60 years of age, with a Breast Cancer–Free Interval rates of 94.9% with ARIMIDEX® and 88.2% with Tamoxifen (HR=0.52, P=0.003). However, in women over 60 years of age, there were no significant differences in outcomes noted between the ARIMIDEX® and Tamoxifen groups. The incidence of invasive contralateral breast cancer was reduced by 45% (HR=0.55, P=0.03) in the ARIMIDEX® group, compared to Tamoxifen group. Adverse events were less common with ARIMIDEX® compared to Tamoxifen. The authors concluded that for postmenopausal women with DCIS treated with lumpectomy and radiation, the 10 year Breast Cancer–Free Interval rates are significantly higher with 5 years of ARIMIDEX® than Tamoxifen and ARIMIDEX® may also be a consideration for those women, who are concerned about the risk of thromboembolic events and uterine cancer with Tamoxifen treatment. Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Margolese RG, Cecchini RS, Julian TB, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA500)

Role of Radiotherapy in Elderly Patients with Low Risk Breast Cancer Following Breast Conserving Surgery

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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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. The National Surgical Adjuvant Breast and Bowel Project (NASBP) protocols B-04 and B-06 have clearly established, after more than a 2 decades of evaluation and follow up that, in Stage I and II breast cancer, there is no significant difference in either distant Disease Free or Overall Survival between the breast conserving surgery and breast removal surgery (Mastectomy). This data established breast-sparing surgery as the preferred local-regional procedure. Radiotherapy after breast-conserving surgery significantly decreases the risk of local recurrence and improves breast cancer–specific survival in certain subgroups of patients. Under ideal circumstances, approximately 70% of the patients can be treated with breast conserving surgery and the risk factors for local recurrences include younger age, high tumor grade, negative hormone receptor status, lymphovascular invasion, extensive intraductal component and positive surgical margins. According to the American Cancer Society, 42% of all invasive breast cancers in the US occur in women 65 years of age or older. These patients may have associated comorbidities and may therefore be appropriate candidates for breast-sparing surgery (rather than mastectomy), as post-op recovery time is shorter. Elderly patients often present with breast tumors that are hormone receptor positive and indolent. Whether women 70 years of age or older with early stage breast cancer need radiotherapy after breast conserving surgery, was addressed by the CALGB cooperative group ( CALGB 9343) and it was noted that the addition of radiation did not improve Overall Survival or distant Disease Free Survival, although there was some improvement in locoregional recurrence rate.

The authors in PRIME II study evaluated local control outcomes in elderly women with early stage breast cancer, at low risk of local recurrence at 5 years, by avoiding whole-breast radiotherapy, following breast conserving surgery. In this Phase III randomized trial, 1326 patients 65 years or older, with low risk early breast cancer, who had undergone breast conserving surgery and were receiving adjuvant hormonal treatment, were randomly assigned to receive whole-breast irradiation (N=658) or no further therapy (N=668). Low risk was defined as tumors T1–T2 up to 3 cm in greatest dimension, clear surgical margins, negative axillary nodes and positive hormone receptors. Either lymphovascular invasion or grade 3 tumor histology was permitted, but not both. The primary endpoint was ipsilateral breast tumor recurrence. After median follow up of 5 years, ipsilateral breast tumor recurrence was 1.3% in women assigned to whole-breast radiotherapy and 4.1% in those assigned no radiotherapy (P=0•0002). There was however no differences in regional recurrence, contralateral breast cancers, distant metastases or new breast cancers, noted between the two groups. The 5-year Overall Survival was similar in both groups 93•9% (P=0•34). The authors concluded that the 5-year ipsilateral breast tumor recurrence is probably low enough that radiotherapy could be avoided in a subset of elderly patients with low risk breast cancer following breast conserving surgery. Kunkler IH, Williams LJ, Jack WJ, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial. Lancet -Oncol. 2015;16:266-273

ABRAXANE® Superior to TAXOL® in High Risk Breast Cancer Including Triple Negative Tumors

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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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Taxanes, which include TAXOL® (Paclitaxel) and TAXOTERE® (Docetaxel) have an important role in the treatment of breast cancer and have been shown in numerous clinical studies to improve survival in patients with early-stage breast cancer and select group of patients with metastatic breast cancer. ABRAXANE® (Nab-paclitaxel) is a solvent free, albumin-encapsulated nanoparticle formulation of the taxane, Paclitaxel. By virtue of its formulation, unlike TAXOL®, hypersensitivity reactions are uncommon with ABRAXANE® and can therefore be rapidly infused and premedications are not needed. Further, higher tumor drug concentrations are achieved with ABRAXANE® compared to conventional Paclitaxel (TAXOL®). Previously published studies have shown that ABRAXANE® is superior to TAXOL® in metastatic breast cancer. GeparSepto trial is a randomized phase III study in which weekly ABRAXANE® was compared head to head with weekly TAXOL® in a neoadjuvant setting. This study enrolled 1204 treatment naïve, high risk patients, with clinical T2-T4d invasive breast carcinoma. Eligible patients included those with unilateral, bilateral, operable or inoperable breast cancer. The median age was 49 years, median tumor size was 3 cm, 23% of the patients had triple-negative disease and 33% had HER-2 positive tumors. Patients were randomized 1:1 to receive either ABRAXANE® 125 mg/m2 IV or TAXOL® 80 mg/m2 IV, weekly for 12 weeks followed by 4 cycles of Epirubicin 90 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV. Patients with HER-2 positive tumors also received HERCEPTIN® (Trastuzumab) and PERJETA® (Pertuzumab). The primary endpoint was pathologic Complete Response (pCR), defined as absence of microscopic residual invasive or noninvasive viable tumor cells in all resected specimens of the breast and axilla. This endpoint was chosen because pathologic Complete Response serves as a surrogate marker for long-term efficacy and outcomes. In this trial, the researchers noted a pathologic Complete Response rate of 38% with ABRAXANE® compared to 29% with TAXOL® (P<0.01). On subgroup analysis, this benefit was even more evident in patients with triple negative breast cancer (N=275), with a pCR rate of 48.2% in the ABRAXANE® group compared with 25.7% in the TAXOL® group (P <0.001). The incidence of peripheral neuropathy was higher in the ABRAXANE® group compared to TAXOL® group and this was attributed to higher weekly doses of ABRAXANE® administered. It is felt that a lower dose of weekly ABRAXANE® (100 mg/m2) would result in a decrease in the incidence of peripheral neuropathy, without compromising efficacy. The authors concluded that ABRAXANE® is superior to TAXOL® in early stage, high risk patients with breast cancer and this benefit is even more evident in those patients with triple negative disease, which comprises about 15% of all breast cancers. Untch M, Jackisch C, Schneeweiss A, et al. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S2-07.

Goserelin for Ovarian Protection during Adjuvant Chemotherapy for Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. 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 is an important additional perk and prevention of Premature Ovarian Failure with ZOLADEX® may be a consideration not only in premenopausal patients with hormone receptor positive breast cancer but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy. Moore HC, Unger JM, Phillips K, et al. N Engl J Med 2015; 372:923-932

Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic 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, 232,000 new cases of invasive breast cancer will be diagnosed in 2015 and about 40,000 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. Trastuzumab 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. Despite this benefit, majority of these patients develop progressive disease within 18 months. The tumors in these patients continue to express HER2 although the lower sensitivity to HER2 targeted agents has been attributed to HER2 independent escape mechanisms. Treatment strategies for this patient population have included switching chemotherapy in subsequent lines of treatment and continuing HERCEPTIN®, combining another HER2 targeted agent, Lapatinib (TYKERB®) with Capecitabine (XELODA®) and dual HER2 inhibition with a combination of HERCEPTIN® and TYKERB®. PERJETA® (Pertuzumab) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to HERCEPTIN® and prevents the dimerization of HER2 with HER3 receptor. PERJETA® stimulates antibody-dependent, cell-mediated cytotoxicity similar to HERCEPTIN®. By combining HERCEPTIN® and PERJETA®, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy, as was demonstrated in early phase trials. The CLEOPATRA trial is a phase III study in which 808 treatment naive HER positive metastatic breast cancer patients, were randomly assigned to receive either HERCEPTIN® plus Docetaxel or this two drug combination given along with PERJETA®. PERJETA® was given as an 840 mg loading dose followed by a 420 mg maintenance dose, HERCEPTIN® was given as an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose and Docetaxel was given at 75 mg/m2 for at least 6 cycles. Treatment was administered every 3 weeks and continued until disease progression. The primary end point of this study was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety. A previous analysis performed in May 2012 showed that the addition of PERJETA® to the combination of HERCEPTIN® and Docetaxel significantly prolonged Progression Free Survival compared to HERCEPTIN® plus Docetaxel alone (18.5 months vs 12.4 months) but the median overall survival had not been reached then. In this final Overall Survival analysis, at a median follow up of 50 months, median Overall Survival was 56.5 months with the PERJETA® combination compared to 40.8 months in the non-PERJETA® group (hazard ratio [HR] = 0.68; P<0.001). This meant that adding PERJETA® to HERCEPTIN® and Docetaxel increased the median Overall Survival by 15.7 months. The increase in Progression Free Survival by 6.3 months with the PERJETA® combination, was again maintained (HR = 0.68, P < 0.0001), at the time of the final analysis. The median duration of response was 20.2 months with the PERJETA® combination compared to 12.5 months in the non-PERJETA® group. The incidence of symptomatic left ventricular dysfunction as well as declines in left ventricular ejection fraction, were rare and similar between the two treatment groups. Based on the CLEOPATRA study, women with HER positive metastatic breast cancer should be considered candidates, for treatment with a combination of PERJETA®, HERCEPTIN® and Docetaxel. Swain S, Baselga J, Kim S, et al. N Engl J Med 2015; 372:724-734