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 lifetime. Approximately, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 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 Therapy (BCT) and Breast Removal Surgery (Mastectomy). This data established Breast Conserving Therapy (BCT) as the preferred local-regional procedure. These trials however often excluded elderly patients or patients with co-morbidities. Radiotherapy after breast- conserving surgery significantly decreases the risk of local recurrence and improves Breast Cancer Specific Survival (BCSS) in certain subgroups of patients. 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 co-morbidities and may therefore be appropriate candidates for breast- conserving surgery rather than mastectomy. These patients also have better outcomes, as post-op recovery time is shorter. There is however limited data to confirm these findings, as most studies evaluated limited numbers of patients, lacked long term follow up and the cause of death in these patients could not be clearly determined.

To further address this question, the authors in this study compared breast-conserving surgery plus radiation therapy (BCT) with Mastectomy, for Breast Cancer Specific (BCSS) and Overall Survival (OS), in a population-based study of 129,692 breast cancer patients without metastatic disease, in the Netherlands. Patients were selected from the Netherlands Cancer Registry, who had T1-2, N0-2, M0 breast cancer, diagnosed between1999 and 2012. Patients were divided into two time cohorts: those diagnosed between 1999 and 2005 (long term follow up), and those diagnosed between 2006 and 2012, (contemporary adjuvant systemic therapy). The influence of prognostic factors such as age, stage, adjuvant systemic therapy, hormonal and HER2 receptor status and co-morbidities was studied in these two groups of patients, in order to identify possible prognostic factors, that might predict patient groups, who could benefit the most from Breast Conserving Therapy (BCT). Information on the cause of death was obtained from Statistics Netherlands, also known as the Dutch Central Bureau of Statistics.

It was noted that for patients in the long-term follow up cohort, Breast Conservation Therapy was associated with a statistically significant improvement in Breast Cancer Specific Survival and Overall Survival compared to Mastectomy in all T1-2, N0-2 stages. For patients diagnosed between 2006 to 2012 (contemporary adjuvant systemic therapy), Breast Conserving Therapy was again associated with a statistically significant improvement in Breast Cancer Specific Survival and Overall Survival for patients in the T1-2, N0-1 stage but not those with T1-2, N2 disease, and in this later group, Breast Cancer Specific Survival (BCSS) with conservation therapy was equal to that with mastectomy. Subgroup analyses in the T1-2, N0-1 subset showed superior BCSS with breast conservation in patients older than 50 years, those who did not receive chemotherapy and those who had co-morbid conditions, irrespective of hormone receptor or HER2 status. The Overall Survival (OS) results were similar. Among patients younger than 50 years of age without co-morbidities, and those who received chemotherapy, BCSS with breast conservation was equal to that with mastectomy, but OS was better with Breast Conservation Therapy than with Mastectomy.

It was concluded that in this large population of “real world” patients as seen in daily clinical practice, Breast Conserving Therapy is associated with superior Breast Cancer-Specific and Overall Survival when compared to Mastectomy in patients over 50 years of age, T1-2, N0-1 M0 stage, patients who had not received chemotherapy and patients with co-morbidities. This benefit was confirmed for patients in both time cohorts. This study information allows the Health Care Provider to decide which type of surgical treatment is best suited for some subtypes of Breast cancer. Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients. Lagendijk M, van Maaren MC, Saadatmand S, et al. ECCO2017 European Cancer Congress. Abstract number: 4LBA

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. Cancer Care Ontario and ASCO convened a Working Group and Expert Panel and following a systematic review of the literature, developed evidence-based recommendations regarding the use of bisphosphonates and other bone-modifying agents, as adjuvant therapy, for patients with breast cancer. These guidelines are based on several important findings noted in previously published studies and in the more recently published Oxford Overview (Early Breast Cancer Trialists’ Collaborative Group) analysis of individual patient data.

1) Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with non-metastatic breast cancer (including those with natural menopause or menopause induced by ovarian suppression or ablation)

2) The absolute benefit with adjuvant bisphosphonates was greater in patients who were at a higher risk of recurrence, and almost all clinical trials were conducted in patients who also received systemic therapy.

3) Most studies evaluated ZOMETA® (Zoledronic acid) or BONEFOS® (Clodronate), and there was extremely limited data for other bisphosphonates. Although XGEVA® (Denosumab) was found to reduce fractures, long-term survival data is awaited.

The following is a summary of the panel’s recommendations:

Recommendation 1

a) Administration of bisphosphonates as adjuvant therapy should be considered for postmenopausal patients with breast cancer (including patients who are premenopausal before treatment and have menopause induced by ovarian suppression as detailed in Recommendation 5) deemed candidates for adjuvant systemic therapy.

b) The final decision of whether or not to administer bisphosphonates should be made during consultation between the patient and oncologist, taking into account patient and disease characteristics, including the risk of recurrence, and weighing the potential benefits and risks.

Recommendation 2

a) Zoledronic acid and Clodronate are the recommended bisphosphonates for adjuvant therapy in breast cancer.

b) There is a need for more information comparing different agents and schedules, and it is recommended that such trials be conducted to establish the utility and optimal administration of other bisphosphonates for adjuvant therapy.

Recommendation 3

a) There is insufficient evidence at this time to make any recommendation regarding the use of Denosumab in the adjuvant setting.

b) It is recommended that studies directly comparing Denosumab with bisphosphonates and evaluating administration schedules, be conducted.

Recommendation 4

a) For patients who will receive adjuvant bisphosphonates (Recommendation 1), Zoledronic acid 4 mg IV over 15 minutes (or longer) every 6 months for 3 to 5 years or Clodronate PO 1,600 mg daily for 2 to 3 years is recommended. Different durations may be considered.

b) More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations.

Recommendation 5

For purposes of adjuvant bisphosphonate use, the definition of menopause should include natural menopause (at least 12 months of amenorrhea prior to initiation of chemotherapy or endocrine therapy) and menopause induced by ovarian ablation or suppression (but not the cessation of menses due to chemotherapy alone). In women aged 60 years or less with a previous hysterectomy and ovaries left in place, Luteinizing Hormone, Follicle Stimulating Hormone and Serum Estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy, to receive adjuvant bisphosphonates.

Recommendation 6

a) A dental assessment is recommended prior to commencement of bisphosphonates, where feasible, and any pending dental or oral health problems should be dealt with prior to starting treatment, if possible. Patients should be informed of the risk of developing osteonecrosis of the jaw, especially with tooth extractions and other invasive dental procedures. Patients should inform their dental practitioner of their treatment. Patients with suspected osteonecrosis of the jaw should be referred to a dental practitioner with expertise in treating this condition. Recent guidelines or position papers by groups such as the International Task Force on Osteonecrosis of the Jaw, the American Association of Oral and Maxillofacial Surgeons, and the American Dental Association should be consulted.

b) Patients should have Serum Calcium measured prior to starting treatment. Patients receiving intravenous bisphosphonates (Zoledronic acid) should be monitored for renal function, prior to starting this treatment and for Serum Calcium and increase in Serum Creatinine, throughout the treatment period.

c) Calcium and vitamin D supplementation is recommended unless otherwise contraindicated. Oral bisphosphonates and Calcium should not be taken concurrently. Several monographs suggest an interval of at least 2 hours to allow for maximum absorption.

d) Symptoms such as ocular pain or loss of vision may be due to serious inflammatory conditions such as uveitis or scleritis and should be promptly evaluated by an ophthalmologist.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. DOI: 10.1200/JCO.2016.70.7257 Journal of Clinical Oncology – published online before print March 6, 2017

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