Breast Cancer Updates: Conventional and Integrative Medicine · favorable biology, endocrine...

Breast Cancer Updates: Conventional and Integrative MedicineChristina M Shannon, ND, FABNOClinical Director for Naturopathic Medicine, Cancer Treatment Centers of America - MRMC

Conventional Updates

v  Surgical Margins v  DCIS & Margins with BCS and Mastectomy v  Molecular Subtyping v  Dual HER2 Blockade

•  © 2016 Rising Tide

Integrative Oncology Updates

v Support Post Surgery v Melatonin

v Outcomes v Physical Activity v Vitamin C

v Long Term Effects v Yoga & Fatigue v Supervised Exercise & Fatigue v Diet, Physical Activity & Cardiovascular v Insomnia and Cognitive Behavioral Therapy v Exercise and AI induced arthralgia

© 2016 Rising Tide

Surgical Margins

•  A multidisciplinary consensus panel

•  meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR)

•  From a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.

•  Harness JK, Giuliano AE, Pockai BA, Downs-Kelly E. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Ann Surg Oncol. 2014 Oct;21(10):3192-7. doi: 10.1245/s10434-014-3957-2. Epub 2014 Aug 1.

© 2016 Rising Tide

Surgical Margins

Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons.

•  Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR (ipsilateral breast tumor recurrence) compared to negative margins.

© 2016 Rising Tide

Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons.

•  This increased risk is not mitigated by favorable biology, endocrine therapy or a radiation boost.

•  More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR. There is no evidence that more widely clear margins reduce IBTR for young patients, unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

Surgical MarginsMargins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Conclusion

The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease healthcare costs.

© 2016 Rising Tide

DCIS and Surgical Margin Width of BCS & Recurrence

• Retrospective analysis of women who underwent breast conserving surgery (BCS) from 1978 – 2010. Median age was 57 years, range 20 – 92)

• 2996 cases identified, median follow-up was 75 months and the range was 0 – 30 years.

• 732 woman were followed for ≥ 10 years.

• Zee KJ Van, Subhedar P, Olcese C, Patil S, Morrow M. Relationship Between Margin Width and Recurrence of Ductal Carcinoma In Situ: Analysis of 2996 Women Treated With Breast-conserving Surgery for 30 Years. Ann Surg. 2015;262(4):623-631. doi:10.1097/SLA.0000000000001454. •  © 2016 Rising Tide

DCIS and Surgical Margin Width of BCS & Recurrence

Results:

•  Among those not receiving radiation (RT), the association of wider margins and lower recurrence was highly significant (P=0.0003).

•  The association was not significant among those who received RT (P=0.99)

10 Year Recurrence & Differential Effect of Margin Width

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

< 1mm 1-9 mm ≥ 10 mm

Recurrence Risk, No Radiation

Recurence Risk, Radition

DCIS and Surgical Margin Width of BCS

& Recurrence

Results:

•  Larger margins in women not receiving RT are significantly associated with a lower rate of recurrence.

•  Wider margins may be not be necessary in those receiving radiation therapy.

© 2016 Rising Tide

Impact of Margin Status on Local

Recurrence Post Mastectomy for Pure DCIS

•  N = 142 women who underwent mastectomy and no radiation therapy for pure ductal carcinoma in situ (DCIS).

•  The largest series of patients with DCIS and positive mastectomy margins (21).

•  21 had + margin, 23 had close margins (≤ 2 mm) and 98 had negative margins.

•  Childs SK, Chen Y-H, Duggan MM, et al. Impact of margin status on local recurrence after mastectomy for ductal carcinoma in situ. Int J Radiat Oncol Biol Phys. 2013;85(4):948-952. doi:10.1016/j.ijrobp.2012.07.2377.

© 2016 Rising Tide



0%

1%

2%

3%

4%

5%

6%

Positive Margin ≤ 2 mm > 2 mm High Grade Disease





•  The primary endpoint was local recurrence defined as recurrence of the chest wall; regional and distant recurrence were secondary endpoints.

•  The low rate of recurrence indicates that post mastectomy radiation is likely not warranted in this patient population.

© 2016 Rising Tide

Oncotype DX vs MammaPrint oncotypedx.com & agendia.com

Oncotype DX MammaPrint

Calculation Panel of 21 genes in tumor tissue. A recurrence score is calculated from the gene expression results.

Designed by evaluating the genome of 78 patients with breast cancer with known outcomes. The result was the identification of 70 genes that were predictive of recurrence risk.

Patient population •  Stage I or II •  ER+ •  Node negative/1-2 + nodes

•  ER+/- •  HER2+/- •  Up to 3 positive nodes

Scores Low Risk Score is 0 – 18 6.8% average risk (95% CI: 4.0%-9.6%) Intermediate Risk Score 14.3% average risk (95% CI: 8.3% - 20.3% High Risk Score is 32 – 100 30.5% average risk (95% CI: 23.6%-37.4%)

Low Risk Results ~10% chance (95% CI 4-15) of cancer recurrence within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy High Risk Results ~29% chance (95% CI 22-35) of cancer recurrence within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy

National Comprehensive Cancer Network (NCCN) Guidelines

Yes Acknowledged July 2015 by NCCN for it’s ability to predict prognosis.

Molecular Subtyping & Pathologic Complete Response

Correlation between the pathologic complete response (pCR) rate after neoadjuvant chemotherapy and long-term outcome (distant metastases-free survival [DMFS]) in patients with early-stage breast cancer (ESBC) using BluePrint and Mammaprint.

Glück S, de Snoo F, Peeters J, Stork-Sloots L, Somlo G. Molecular subtyping of

early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat. 2013;139(3):759-767. doi:10.1007/s10549-013-2572-4.

Molecular Subtyping & Pathologic Complete Response

•  BluePrint and MammaPrint molecular subtyping versus clinical subtyping using immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) for the determination of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2).

© 2016 Rising Tide

•  N = 437 patients in four neoadjuvant chemotherapy trials.

•  Luminal A-type (MammaPrint Low Risk) patients have a good prognosis with excellent survival and do not seem to benefit from chemotherapy.

•  We observed marked benefit in response and DMFS to neoadjuvant treatment in patients subtyped as HER2-type and Basal-type.

•  BluePrint with MammaPrint helps to improve prognostic estimation and the choice of therapy versus IHC/FISH in ESBC.

© 2016 Rising Tide

Blue Print Molecular Subtypes Molecular Subtype

Luminal A Luminal B HER2 Basal

Histology Lower Grade ER+

Higher Grade ER+

High Grade High grade, sheet like necrosis

Markers Strong ER+, PR+/- HER2-, Low Ki67

Weak ER+, PR+/- HER2+/-, High Ki67

HER2+ ER+/-, PR+/-

ER-, PR-, HER2- Triple Negative

Prognosis Good Intermediate Worse Worse, BRCA1 especially when diagnosed < 50 yrs

Response to Chemotherapy

Lower pCR = 6%

Intermediate pCR = 10%

Higher pCR = 47%

Higher pCR = 37%

Targeted Therapies

Endocrine Endocrine HER2 targeted therapies

Dual HER2 for Metastatic Disease

•  Dual HER2 Blockade = trastuzumab and pertuzumab

•  Trastuzumab disrupts ligand independent HER2 signaling.

•  Pertuzumab •  blocks ligand dependent HER2

heterodimerization with HER1, HER3, HER4 •  inhibits HER2:HER3 dimer formation •  Mediates antibody dependent cell mediated

cytotoxicity © 2016 Rising Tide

Dual HER2 for Metastatic Disease – CLEOPATRA Study

•  Median overall survival 56.5 months (95% confidence interval [CI], 35.8 to not reached) in the group receiving the pertuzumab combination.

•  Compared to 40.8 placebo group. (95% CI, 35.8 to 48.3). A difference of 15.7 months.

Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513.

© 2016 Rising Tide


•  Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed.

•  These were patients who had not received previous treatment of chemotherapy or HER2 directed treatment for the metastatic disease.

© 2016 Rising Tide


•  Median follow-up of 50 months & long term cardiac safety maintained.

•  Diarrhea (46% to 67%; grades 3/4: 5% to 8%) •  nausea (39% to 53%; monotherapy 24%) •  vomiting (13% to 36%; monotherapy 15%) •  decreased appetite (11% to 29%) •  constipation (23%) •  mucositis (20% to 28%) •  stomatitis (17% to 19%)

© 2015 Rising Tide

Pertuzumab Indications Breast cancer, metastatic:

Patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease.

Breast cancer, neoadjuvant treatment:

Neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2-positive, breast cancer (either greater than 2 cm in diameter or node positive)

In combination with trastuzumab and docetaxel (as part of a complete treatment regimen for early breast cancer).

Limitations of use:

Not studied along with doxorubicin-containing regimen

The safety of pertuzumab administered for more than 6 cycles for early breast cancer has not been established.

NeoSphere Trial: Efficacy and safety of neoadjuvant and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer, a randomized, multicenter,

phase 2 trial

Integrative Oncology Updates

v Support Post Surgery v Melatonin

v Outcomes v Physical Activity v Vitamin C

v Long Term Effects v Yoga & Fatigue v Supervised Exercise & Fatigue v Diet, Physical Activity & Cardiovascular v Insomnia and Cognitive Behavioral Therapy v Exercise and AI induced arthralgia

© 2016 Rising Tide

Naturopathic Support with Treatment:The MELODY Trial

•  Randomized, double blind, placebo-controlled

trial

•  Women 30 – 75 years undergoing surgery for breast cancer without signs of depression 1 week prior to surgery. N = 54

Hansen M V, Andersen LT, Madsen MT, et al. Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat. 2014;145(3):683-695. doi:10.1007/s10549-014-2962-2

© 2016 Rising Tide

MELODY Trial •  Intervention group received 6 mg oral

melatonin, control group received placebo for 3 months.

•  The primary outcome was the incidence of depressive symptoms as measured by Major Depression Inventory (MDI).

•  Secondary outcomes were area under the curve (AUC) for the subjective parameters of anxiety, sleep, general well being, fatigue, pain and sleepiness.

•  Relative risk 0.25 [95 % CI 0.077-0.80]), giving a

NNT of 3.0 [95 % CI 1.7-11.0].

•  No significant differences were found between AUC for the subjective parameters. No differences in side effects were found (P = 0.78). Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery.

Melatonin Group Placebo

•  3/27 (11%) developed depressive symptoms

•  9/20 (45%)

Breast Cancer Outcomes & Physical Activity

•  Systematic review and meta-analysis of studies

investigating the association between physical activity and breast cancer recurrence and death.

•  22 prospective cohort studies with average follow-up ranging from 4.3 to 12.7 years with a median and mean of 8 years. Total N = 123,574

© 2016 Rising Tide

Breast Cancer Outcomes &Physical Activity

All Cause Death HR (95% CI)

Breast Cancer Death HR (95% CI)

Recurrence

Pre-diagnosis Physical Activity (5 years before)

0.71 (0.63-0.81) 0.84 (0.71 –1.00) 0.72 (0.56-0.91) (more recent PA and lifetime)

Post-diagnosis Physical Activity

0.52 (0.43 – 0.64) 0.59 (0.45 – 0.78)

Meeting recommended Physical Activity post-diagnosis

0.54 (0.38 – 0.76) 0.67 (0.50 – 0.90) 0.79 (0.63-0.98)

All Cause Death Risk Reduction

Breast Cancer Death Risk Reduction

Post Diagnosis Physical Activity & BMI

Risk reduction for patients with BMI < 25 and ≥ 25.

Risk reduction for patients with BMI < 25 and ≥ 25.

Post Diagnosis Physical activity & Menopausal Status

Benefits seen in both pre and postmenopausal but greater risk reduction for postmenopausal

Benefits seen in both pre and postmenopausal.

Post Diagnosis Physical activity & ER/PR Status

Greatest risk reductions for ER+ and ER-/PR- compared to ER- and ER+/PR+

Greatest risk reduction for ER+/PR+ and ER-/PR-

Breast Cancer Outcomes & Physical Activity

•  Limitations are that the majority of studies did not control for confounders adequately and only 41% controlled for stage, nodal status, age and treatment.

Lahart IM, Metsios GS, Nevill AM, Carmichael AR. Physical activity, risk of death and recurrence in breast cancer survivors: A systematic review and meta-analysis of epidemiological studies. Acta Oncol (Madr). April 2015. http://www.tandfonline.com/doi/abs/10.3109/0284186X.2014.998275. Accessed September 28, 2015.

© 2016 Rising Tide

Take Home Message on Exercise

Effect estimates of the associations between physical activity and all cause death and breast cancer related death must be treated with caution due to heterogeneity that was identified in the studies.

However, the results do support the role of physical activity in potentially improving and extending overall survival after a breast cancer diagnosis.

Lifestyle Factors in Survivorship:

Vitamin C Intake

• A meta-analysis, 10 prospective studies looking at the association between vitamin C supplement use and dietary vitamin C intake and breast cancer specific mortality and total mortality met inclusion criteria

• Harris HR, Orsini N, Wolk A. Vitamin C and survival among women with breast cancer: a meta-analysis. Eur J Cancer. 2014;50(7):1223-1231. doi:10.1016/j.ejca.2014.02.013.

Results

Total Mortality Relative Risk, 95% CI

Breast Cancer Mortality Relative Risk, 95% CI

Post Diagnosis Vitamin C Supplement Use Shanghai Breast Cancer Study used 400 mg or less and Swedish Mammography Cohort’s most frequent dose was 1,000 mg

.81 (0.72 - 0.91)

.85 (.74 – 0.91)

100 mg/day increase in dietary vitamin C use

.73 (0.59 - 0.89)

.78 (0.64 – 0.94)

• Post diagnosis vitamin C supplement use may be associated with reduced risk of total mortality and possibly breast cancer mortality.

• Dietary vitamin C intake was statistically significantly associated with a reduced risk of total mortality and breast cancer specific mortality.

Lifestyle Factors in Survivorship: Yoga, Fatigue & Vitality

• A randomized controlled 3-month trial

• 200 breast cancer survivors • stage 0 to IIIa from 27-76 years was assigned to either 12 weeks of 90-minute twice per week hatha yoga classes or a wait-list control.

Kiecolt-Glaser JK, Bennett JM, Andridge R, et al. Yoga’s impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2014;32(10):1040-1049. doi:10.1200/JCO.2013.51.8860.

© 2016 Rising Tide

Lifestyle Factors in Survivorship: Yoga

• Measured lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β)

• Measured scores on the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the vitality scale from the Medical Outcomes Study 36-item Short Form (SF-36), and the Center for Epidemiological Studies-Depression (CES-D) scale.

© 2016 Rising Tide

Lifestyle Factors in Survivorship: Yoga

•  Immediately following treatment fatigue was not lower but vitality was higher.

•  At 3 months post intervention, fatigue was lower and vitality was higher.

•  IL-6, TNF alpha and IL-1 beta •  were lower in yoga group

•  Depression was not effected © 2016 Rising Tide

Lifestyle Factors in Survivorship: Supervised Exercise

• Systematic Review and Meta-analysis

• Goal was to determine the effect of supervised exercise on cancer related fatigue (CRF) in breast cancer survivors.

• Meneses-Echávez J, González-Jiménez E, Ramírez-Vélez R. Effects of supervised exercise on cancer-related fatigue in breast cancer survivors: a systematic review and meta-analysis. BMC Cancer. 2015;15(1):77. doi:10.1186/s12885-015-1069-4.

Lifestyle Factors in Survivorship: Supervised Exercise

• Exercise was defined as “any body movement that causing an increase in energy expenditure that involved a planned or structured movement of the body performed in a systematic manner in terms of frequency, intensity and duration designed to maintain or enhance health outcomes.”

• Tai-Chi, massage, manipulation and cognitive behavioral interventions excluded.

Lifestyle Factors and Cancer Related Fatigue: Supervised Exercise

•  Average of 55.2 years of age, Predominantly

non-Hispanic whites

•  9 studies included, N=1156, randomized trials without restrictions on stage of disease. Conventional care was no participation in an exercise intervention program.

•  67% or 6 studies were conducted during active treatment including chemotherapy and radiotherapy

© 2016 Rising Tide

Lifestyle Factors and Cancer Related Fatigue: Supervised Exercise

•  Aerobic training was described in all studies •  6 studies included resistance training •  Stretching exercises in 1 study

•  Supervised exercise had a mean length of 21.4 weeks (SD of 15.8 weeks)

•  Mean Duration of 44.3 minutes (SD 15.2) •  Average of 2.5 sessions per week

•  No major adverse events reported

© 2016 Rising Tide

Supervised Exercise

• Results: •  Pooled analysis showed that supervised

aerobic exercise was statistically more effective than conventional care in improving CRF among breast cancer survivors. (SMD = -.51, 95% CI -0.81 to -0.21) with statistical heterogeneity, P = 0.001)

Supervised Exercise •  Sub-analysis:

• Supervised exercise during active treatment showed significant benefit in CRF. (SMD = -0.66, 95% CI -1.08 to -0.23) P = 0.002

• 4 studies implemented supervised exercise in breast cancer post treatment and did not show statistical significance (SMD= -0.25, 95% CI -0.55 to 0.05) Most of these studies recruited people beyond 5 years since primary cancer diagnosis.

• Resistance training significantly improved CRF (SMD = -0.55; 95% CI, -1.09 t0 -0.01)

Lifestyle Factors in Survivorship: Diet & Physical Activity

& Cardiovascular Health

•  Obese and overweight breast cancer survivors were enrolled in a trial of a low calorie diet and exercise changes.

Travier N, Fonseca-Nunes A, Javierre C, et al. Effect of a diet and physical activity intervention on body weight and nutritional patterns in overweight and obese breast cancer survivors. Med Oncol. 2014;31(1):783. doi:10.1007/s12032-013-0783-5.

© 2016 Rising Tide



•  Participants exercised for 75 minutes, twice weekly

•  Received 60 minutes weekly dietary counseling to reduce total calories, saturated fat, and carbohydrate intake.

•  112 started and 37 completed the program.

© 2016 Rising Tide



•  90% participation •  Significant weight loss of 5.6 +/- 2.0 kg •  Significant ↓ BMI •  Total calories ↓ by 25% •  Total Fat ↓ by 35% •  Saturated fat ↓ by 37% •  Carbohydrates ↓ by 21% •  Quality of Life and Cardiorespiratory

Fitness significantly improved. © 2016 Rising Tide


Insomnia and Cognitive Behavioral Therapy

•  Prospective, longitudinal, randomized, controlled trial. N = 56 Breast Cancer Survivors with chronic insomnia

•  Randomly assigned to Cognitive Behavioral

Therapy weekly for 6 sessions or placebo behavioral therapy for Insomnia

Matthews EE, Berger AM, Schmiege SJ, et al. Cognitive behavioral therapy for insomnia outcomes in women after primary breast cancer treatment: a randomized, controlled trial. Oncol Nurs Forum. 2014;41(3):241-253. doi:10.1188/14.ONF.41-03AP.

© 2016 Rising Tide

Lifestyle Factors in Survivorship: Insomnia and Cognitive Behavioral

Therapy •  Main outcomes measures were sleep outcomes

including sleep efficiency, sleep latency, total sleep time, wake after sleep onset, number of nightly awakenings at baseline, post intervention, 3 and 6 month follow-ups.

•  The individual sessions included education on sleep restriction, stimulus control, sleep hygiene education and CBT from existing protocols. Patients maintained a sleep diary.

© 2016 Rising Tide


Insomnia and Cognitive Behavioral Therapy

•  Nurse delivered CBT improved sleep efficiency and latency and was maintained during follow-up.

•  Secondary measures of insomnia, physical and

cognitive function and positive sleep attitudes improved.

•  QOL, fatigue and mood were not improved.

© 2016 Rising Tide

Lifestyle Factors in Survivorship: Exercise and AI Induced Arthralgia

• Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors.

• N= 121

• Average age = 61 years • 60% had stage I breast cancer • Average time between enrollment & diagnosis was 3 years. Irwin ML, Cartmel B, Gross CP, et al. Randomized Exercise Trial of Aromatase Inhibitor-Induced Arthralgia in Breast Cancer Survivors. J Clin Oncol. 2014:JCO.2014.57.1547 - . doi:10.1200/JCO.2014.57.1547.

© 2016 Rising Tide

Lifestyle Factors in Survivorship: Exercise and AI Induced Arthralgia•  This was a yearlong exercise intervention

•  150 minutes per week of aerobic exercise home based

•  Supervised strength training twice per week compared to usual care only.

•  Worst joint pain scores decreased by 29% at 12 months in the exercise group, compared to a 3% reduction for usual care.

•  Pain severity and interference also decreased significantly at 12 months with exercise. © 2016 Rising Tide

Take Home Messages

v  Conventional treatment for breast continues to adapt and become refined to allow for the least amount of intervention for the best outcome.

v  The scientific evidence continues to grow in support of the long standing practices of naturopathic medicine such diet, mind body practices and physical activity to improve the outcome and lives of women diagnosed with breast cancer.

v Additional slides and information at the

end.

v Thank you! Questions.

Management of the Axilla Study Patient Population Control Group Intervention Group Outcomes

ACOSOG Z11 Published 2011

Clinical T1/T2 N0 tumors with 1 or 2 positive SLNs ≥ 3 SNL were excluded from the study.

Lumpectomy + WBRT w/o Axillary Field +ALND

Lumpectomy+ WBRT w/o Axillary Field

•  At 6.3 years no differences were found

AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery) Published 2014

Clinical T1/T2 with no palpable lymphadenopathy At least 1 positive SNL

BCS w/ WBRT or Mastectomy w or w/o Radiation of the Chest Wall with ALND

BCS w/ WBRT or Mastectomy w or w/o Radiation of the Chest Wall with AxRT

•  No signiMicant difference in 5 year axillary recurrence rate, DFS, OS, QOL

•  Lymphedema occurred more signiMicantly in the ALND

MA.20 Published 2015

IBC tx with BCS and SLNB or AND and who had +ALN or – ALN with high-‐risk features. (most patients had greater than 3 positive nodes)

IBC tx with BCS and SLNB or ALND and who had +ALN or –ALN with high-‐risk features assigned to WBRT plus regional node irradiation.

Whole Breast Irradiation Alone.

•  No difference in OS, BC Mortality

•  Subgroup: ER-‐ in the nodal irradiation group had a higher 10 year OS

•  Relative DFS higher in the nodal irradiation group. Again the beneMit was greatest with ER/PR negative tumors

EORTC Published 2015

Central or Medially located tumor w or w/o axillary involvement or Externally located tumor w axillary involvement

Whole Breast Radiation or Thoracic Wall Radiation alone

Whole Breast Radiation or Thoracic Wall Radiation w/ Regional nodal irradiation (RNI) = internal mammary and medial supraclavicular lymph nodes

•  OS survival in the RNI group had marginal beneMit .

•  Small but signiMicant beneMit to DFS, Distant Disease Free Survival (DDFS) and breast cancer mortality.

Considerations in Management of Axilla •  ASCOG Z0011 study was not associated with a clinically significant

number of SLN removed, however in one institution an evaluation of practice patterns shifted to ≥ 4 SLN removed post Z0011.

•  Challenges with Z0011 include inability to meet accrual, remarkably low axillary recurrence (0.9%) and majority of patients received systemic treatment and all received whole breast irradiation.

•  Z0011 post review also found that 19%b had received a third field directed to supraclavicular area and high tangents were used.

•  AMAROS provides an alternative to ALND

•  AMAROS identified sub population of ER- that benefited from nodal irradiation

•  MA.20 only showed marginal benefits with RNI. © 2016 Rising Tide

BOLERO-2 Trial everolimus and exemestane •  Postmenopausal women with HR+ advanced breast cancer with

recurrence/progression during or after treatment with a nonsteroidal aromatase inhibitor (anastrozole or letrozole).

•  Primary endpoint was Progression Free Survival, Overall Survival, Response Rate and Clinical Benefit Rate were secondary endpoints.

•  Everolimus is an mTOR inhibitor and a down stream regular of

progression and endocrine resistance.

•  EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinically meaningful and statistically significant improvement in the primary end point, PFS. An absolute difference in PFS of > 4 months. © 2016 Rising Tide

BOLERO-2 Trial everolimus and exemestane •  Everolimus binds to its protein receptor FKBP12, which directly

interacts with mTORC1 inhibiting its downstream signaling. As a consequence, mRNAs that codify proteins implicated in the cell cycle and in the glycolysis process are impaired or altered, so tumor growth is inhibited. Hence, everolimus inhibits tumor cells' growth and proliferation.

•  mTOR activates ER in a ligand-independent manner.

•  Estradiol suppresses apoptosis inducted by mTOR blockade.

•  Hyperactivation of the mTOR pathway in endocrine therapy resistance breast cancer cells

© 2016 Rising Tide

BOLERO-2 Trial everolimus and exemestane

Adverse Events > 25%

Adverse Events Grade 3/4

•  Stomatitis •  Rash •  Fatigue •  Diarrhea •  Nausea •  Decreased Appetite •  Weight Loss •  Cough

•  Stomatitis •  Fatigue •  Dyspnea •  Anemia •  Hyperglycemia •  Gamma-glutamyltransferase é

(most common grade ¾ AE)

Ø  Despite the increased toxicity the health related quality of life was not worse with the combination.

everolimus and exemestane

•  Naturopathic Management •  Diet

•  Dietary interventions should include recommendations regarding blood sugar control.

•  Prevention of Stomatitis •  Baking soda washes •  MediHoney •  L - Glutamine

•  Diarrhea Management •  L – Glutamine •  Slippery Elm •  Probiotics •  Dietary considerations

© 2016 Rising Tide

References for additional slides:

Giuliano AE, Hunt KK, Ballman K V, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90.

Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303-1310. doi:10.1016/S1470-2045(14)70460-7.

Whelan TJ, Olivotto I a., Parulekar WR, et al. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015;373(4):307-316. doi:10.1056/NEJMoa1415340.

Poortmans PM, Collette S, Kirkove C, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med. 2015;373(4):317-327. doi:10.1056/NEJMoa1415369.

Preeti S, Stempel M, Eaton A, Morrow M, Gemignani M. Do the ASOSOG Z0011 Criteria Affect the Number of Sentinel Lymph Nodes Removed? Ann Surg Oncol. 2015. http://www.annsurgoncol.org/journals/abstract.html?v=0&j=10434&i=-1&a=4698_10.1245_s10434-015-4698-6&doi=. Accessed January 25, 2016.

Mahmoud O, Haffty BG. Regional nodal management in the light of the AMAROS trial. Ann Transl Med. 2015;3(7):88. doi:10.3978/j.issn.2305-5839.2015.02.21.

Yardley D a, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer:

BOLERO- 2 final progression-free survival analysis. Adv Ther. 2013;30(10):870-884. doi:10.1007/s12325-013-0060-1.

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