the neoadjuvant diagnostic workup hope s. rugo, md · undergo axillary lymph node sampling at the...

The Neoadjuvant Diagnostic WorkupHope S. Rugo, MDBreast cancer is the leading cause of cancer death among women worldwide.1 It is estimated that over 230,000 women in the United States will be diagnosed with breast cancer and approximately 40,000 women will die from their disease this year.2 A number of trials have demonstrated that neoadjuvant chemotherapy can improve the rate of breast-conserving surgery, and that the absence of invasive disease in breast and axillary lymph nodes (pathologic complete response, pCR) following treatment correlates with improved outcome compared to patients with residual disease.3,4 A recent meta-analysis confirmed that pCR is much more common in aggressive breast cancer subtypes compared to low proliferative, generally hormone-receptor-positive (HR-positive) disease.5 However, the absence of pCR does not correlate with outcome in these low proliferative tumors, which are effectively treated with hormone therapy following surgery. According to the 2015 National Comprehensive Cancer Network (NCCN) guidelines, preoperative chemotherapy should be considered for women with clinical stage IIA, Stage IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size, and who wish to undergo breast-conserving surgery.6 Neoadjuvant therapy is also increasingly used to test responsiveness to novel therapies or therapeutic combinations. This monograph reviews the neoadjuvant therapy treatment option and the considerations involved.

Clinical considerationsSeveral clinical factors should be considered before administering neoadjuvant chemotherapy prior to primary surgery.7 The most obvious is invasion of local structures such as skin or pectoralis muscle, since reducing the extent of disease will reduce the extent of excision and thus improve surgical outcome. Tumor size is also an important factor; neoadjuvant therapy is more appropriate for larger clinical stage IIA or IIB and T3N1M0 tumors and tumors deemed inoperable due to local extent of disease at the time of diagnosis.6 One benefit of neoadjuvant chemotherapy is that, in appropriately selected patients, it increases eligibility for breast-conserving surgery.3 If breast conservation is feasible and the biology of the tumor merits chemotherapy, neoadjuvant chemotherapy can be initiated to shrink the tumor to try to improve overall cosmetic outcome.8

Inflammatory breast cancer (IBC) is an uncommon, aggressive form of breast cancer that presents with erythema and edema of the dermal layer (peau d’orange) of at least one-third of the skin of the breast due to the blockage of lymphatics by tumor emboli. Tissue biopsy of the skin and underlying mass is recommended but the diagnosis of IBC is based on clinical assessment. Following appropriate staging, patients with inflammatory breast cancer should be treated with neoadjuvant chemotherapy to improve resectability of this disease.9

Impact of biomarkers on treatment decisionsUnderstanding tumor biology is critical for decisions about neoadjuvant therapy. All tumors under consideration should undergo core biopsy to allow full pathologic evaluation. Expression of estrogen and/or progesterone hormone receptors, and expression or gene amplification of HER2/neu along with tumor grade, are the most important initial factors in determining therapeutic options.6 Tumors negative for hormone receptors or positive for HER2 are aggressive subsets that are known to respond to neoadjuvant chemotherapy.7,10 In contrast, HR-positive tumors are more heterogeneous. Tumors with low proliferation are unlikely to respond to neoadjuvant chemotherapy, whereas the more proliferative HR-positive tumors may have a good response.11 Newer gene expression tests may help to determine which cancers have a better chance of responding to neoadjuvant chemotherapy. Both the Oncotype DX recurrence score and the MammaPrint 70-gene expression assay have demonstrated the ability to identify

tumors more likely to achieve pCR. In the neoadjuvant I-SPY 1 trial, tumors that were low risk by the Mammaprint assay had an excellent prognosis despite a low rate of pCR.12 These data suggest that this type of assay might provide important information about which tumors are likely to respond to neoadjuvant chemotherapy and which should be considered for treatment with neoadjuvant hormone therapy or should proceed directly to surgery. Mammaprint has now been incorporated into the I-SPY 2 multicenter neoadjuvant trial as a way to select patients whose tumors have the best chance of responding to neoadjuvant chemotherapy.13 All biopsy samples from newly diagnosed breast cancer should be tested for expression of the estrogen receptor, progesterone receptor, and HER2/neu. Breast cancers that have at least 1% of cells staining positive for ER have historically been considered ER-positive,14,15 but hormone-responsive tumors generally are at least 10% positive. HER2 status can be assessed by measuring the quantity of HER2 cell surface receptors by immunohistochemistry (IHC) or by measuring the ratio of the number of HER2 gene copies to the centromere 17 gene copies (CEP17) using fluorescent in situ hybridization (FISH). Tumor cells are considered HER2-positive by IHC if scored as 3+ with uniform membrane staining for HER2 in 10% or more of tumor cells or have HER2 gene amplification by FISH (single probe, average HER2 copy number ≥6 signals/cells, dual probe HER2/CEP17 ratio ≥2 with an average HER2 copy number of ≥4 signals/cell; dual probe HER2/CEP17 ratio ≥2 with an average HER2 copy number of <4 signals/cell; HER2/CEP17 ratio <2 with an average HER2 copy number >6 signals/cell). High average copy number of HER2 (>6 signals/cell) is considered positive regardless of the HER2/CEP17 ratio. Results of HER2 by IHC scored as 2+ are considered equivocal, and should be retested by FISH. Only those with positive testing by FISH are considered HER2-positive.16

Implications for pretreatment testingBreast magnetic resonance imaging (MRI) may be performed for staging evaluation in patients with newly diagnosed breast cancer to define the extent of breast cancer or to rule out the presence of multifocal or multicentric disease in the ipsilateral breast and to screen the contralateral breast. In general, breast MRI should be considered in women with dense breast tissue, positive axillary nodal status, and occult primary tumor presumed to originate in the breast.17 Breast MRI is useful before neoadjuvant chemotherapy to serve as a baseline examination and after completion of therapy to assess the response to treatment and the potential for breast conservation.18 It is important to note that the false-positive rate on MRI is high and MRI imaging findings alone should not determine surgical decisions. When additional MRI findings raise concern, tissue sampling should be performed prior to the initiation of neoadjuvant chemotherapy.19 Basic workup and staging of invasive breast cancer includes laboratory studies (complete blood count and liver function tests with alkaline phosphatase). Systemic staging should be considered, particularly if signs or symptoms of potential metastatic disease are present and for larger tumors or positive axillary nodes.6 Staging studies should include imaging of the chest, abdomen, pelvis, and bone. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is increasingly performed for systemic staging and is able to evaluate bone and soft tissues. Care must be taken in interpreting FDG-avid sites without CT correlates. Suspicious areas should be biopsied before making a diagnosis of metastatic disease. The NCCN does not recommend systemic staging in patients with Stage I disease without signs or symptoms of metastatic disease.20 Patients for whom treatment will include either anthracyclines or HER2-targeted therapy should undergo baseline cardiac testing with either a multigated radionuclide angiography (MUGA) or echocardiogram (ECHO) due to potential cardiotoxic adverse events.21 Patients diagnosed with breast cancer should be considered for genetic screening based on risk factors assessed during initial consultation.6,22 The presence of a genetic mutation may drive

The Neoadjuvant Diagnostic Workup

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References01. Health and Human Services, Centers for Disease Control and

Prevention, and National Cancer Institute; 2014. Breast cancer statistics. http://www.cdc.gov/cancer/breast/statistics/. Accessed May 10, 2015.

02. American Cancer Society. What are the key statistics about breast cancer? http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. Accessed May 11, 2015.

03. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 2007;94(10):1189-1200.

04. Kuerer HM, Newman LA, Buzdar AU, et al. Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy

predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 1998;176(6):502-509.

05. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384(9938):164-172.

06. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology ([NCCN Guidelines®]): Breast cancer, v.2.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 10, 2015.

07. King TA, Morrow M. Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol 2015 Apr 7. [Epub ahead of print]


decisions for mastectomy rather than breast-conserving surgery, prophylactic contralateral surgery, or prophylactic oophorectomy. Risk factors for genetic mutations outlined by the NCCN include breast cancer diagnosed prior to age 50, bilateral breast cancer, triple-negative breast cancer diagnosed prior to age 60, breast cancer at any age in a patient with a history of ovarian cancer in self or close relative, breast cancer at any age in a patient with Ashkanzi (Eastern European) Jewish ancestry, patients with a history of ovarian cancer at any age, male breast cancer at any age, or a known BRCA mutation in the family.6 Additional mutations can now be screened to identify increased risk of breast cancer; these mutations are evaluated in commercially available genetic testing panels.

Surgical implicationsBreast cancer may present as a radiographic finding or, more commonly for aggressive tumors, as interval findings on self-examination or clinical examination. Initial evaluation should include a diagnostic mammogram and ultrasound. Solid masses visible on ultrasound should undergo core needle biopsy for further evaluation.23 A radiographically dense marker is usually placed at the time of the core biopsy to guide subsequent surgery. Fine needle aspiration can be considered for initial diagnosis of malignancy, and can be used to sample palpable or image-detected axillary nodes.24 Patients without palpable axillary nodes should undergo imaging of their axilla by ultrasound and tissue sampling of visible abnormal nodes.6 Pursuing surgical or excisional breast biopsy over core biopsy is not recommended, particularly in patients under consideration for neoadjuvant chemotherapy. Surgery following neoadjuvant chemotherapy aims to remove all tumor and achieve optimal cosmesis. Often, contralateral breast surgery is carried out in order to improve symmetry. Patients with positive axillary lymph nodes at the time of initial diagnosis should undergo axillary lymph node sampling at the time of definitive breast surgery following neoadjuvant chemotherapy.6 Among patients who are node-positive prior to neoadjuvant chemotherapy, sentinel lymph node biopsy has a false-negative rate greater than 10%.25 Alternatively, patients without evidence of axillary node involvement are candidates for sentinel lymph node biopsy. Sampling the sentinel nodes following neoadjuvant chemotherapy provides excellent local control, suggesting that this surgery can be avoided prior to neoadjuvant therapy.25,26

Fertility preservation Systemic treatment with cytotoxic therapy for breast cancer may impair fertility. This risk is dependent on patient age and treatment regimen. Many studies have shown that child bearing after treatment for breast cancer does not increase the rates of recurrence or death from this disease, provided that standard therapy has been administered.27 It is important to consider fertility preservation prior to breast cancer treatment in young women who want to bear children after their treatment.28 All premenopausal patients with breast cancer for whom chemotherapy has been

recommended should be informed about the potential impact of treatment on fertility and directly asked about their desire for future pregnancy. Premenopausal women interested in preserving fertility should immediately be referred to a fertility specialist who can discuss options for fertility preservation.29 Egg harvesting can generally be conducted over a two-week period and, therefore, does not significantly delay the start of systemic therapy.29 Recent data suggest that ovarian suppression with goserelin during chemotherapy in women with HR-negative disease can preserve ovarian function following treatment.30 This option should be discussed with eligible patients but is not a substitute for freezing oocytes or embryos.

Distress managementDistress management is an important part of the evaluation of a patient with newly diagnosed breast cancer. It is imperative that clinicians screen patients for distress at their initial visit and at appropriate intervals throughout treatment.31 Appropriate referrals should be made to licensed mental health professionals, social workers, counselors, and certified chaplains with experience in cancer care. When the patient exhibits a clinically significant level of distress, a treatment plan should be implemented with the patient, family, and multidisciplinary team.32 Reevaluation of distress should be performed and plan adjustments made as appropriate throughout the patient’s treatment.

New directionsThe association of pCR with long-term outcome has increased interest in studying new agents and combinations in the neoadjuvant setting to determine both effective therapies and the biologic disease subsets most likely to benefit. The I-SPY 2 trial is a multicenter, adaptively randomized phase 2 trial that is testing a series of novel agents in combination with standard chemotherapy to understand the probability of pCR compared to control, and to identify biomarkers that define the patient population whose tumors are most likely to benefit.13 Indeed, the majority of new agents are evaluated in the neoadjuvant setting using a variety of trial designs.33

ConclusionIn summary, to optimize treatment outcomes, oncologists should be familiar with current recommendations for neoadjuvant therapy, including analysis of biomarker expression, genetic screening, and patient preference for breast conservation. Decisions regarding neoadjuvant therapy require a team of specialists, including surgeons, medical oncologists, and radiation oncologists. Additional expertise should be available for psychosocial support and fertility preservation. Clinical trials in the neoadjuvant setting allow us to evaluate novel therapeutics and at the same time evaluate biomarkers to identify the tumor subtypes most likely to benefit, thus advancing the field toward the goal of personalized therapy.

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08. Caudle AS, Kuerer HM. Breast conservation therapy after neoadjuvant chemotherapy: optimization of a multimodality approach. J Surg Oncol 2014;110(1):32-36.

09. Dawood S, Cristofanilli M. What progress have we made in managing inflammatory breast cancer? Oncology (Williston Park) 2007;21(6):673-679.

10. Boughey JC, McCall LM, Ballman KV, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial. Ann Surg 2014;260(4):608-614.

11. Colleoni M, Montagna E. Neoadjuvant therapy for ER-positive breast cancers. Ann Oncol 2012;23 Suppl 10:243-248.

12. Esserman LJ, Berry DA, DeMichele A, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. J Clin Oncol 2012;30(26):3242-3249.

13. Park JW, Liu MC, Yee D, et al. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 trial. 2014 American Association for Cancer Research Annual Meeting. Abstract CT227. Presented April 7, 2014.

14. Allred DC, Carlson RW, Berry DA, et al. NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry. J Natl Compr Canc Netw 2009;7 2009;7(Suppl 6):1-2.

15. Hammond ME. ASCO-CAP guidelines for breast predictive factor testing: an update. Appl Immunohistochem Mol Morphol 2011;19(6):499-500.

16. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31(31):3997-4013.

17. Chen JH, Su MY. Clinical application of magnetic resonance imaging in management of breast cancer patients receiving neoadjuvant chemotherapy. Biomed Res Int 2013;2013:348167.

18. Ojeda-Fournier H, de Guzman J, Hylton N. Breast magnetic resonance imaging for monitoring response to therapy. Magn Reson Imaging Clin N Am 2013;21(3):533-546.

19. Lehman CD, DeMartini W, Anderson BO, Edge SB. Indications for breast MRI in the patient with newly diagnosed breast cancer. J Natl Compr Canc Netw 2009;7(2):193-201.

20. Puglisi F, Follador A, Minisini AM, et al. Baseline staging tests after a new diagnosis of breast cancer: further evidence of their limited indications. Ann Oncol 2005;16(2):263-266.

21. Rochette L, Guenancia C, Gudjoncik A, et al. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 2015;pii: S0165-6147(15)00055-3.

22. Mukherjee A, Rakha EA. Integrating breast cancer genetics into clinical practice. Women’s Health (Lond Engl) 2012;8(1):99-112.

23. Dahabreh IJ, Wieland LS, Adam GP, Halladay C, Lau J, Trikalinos TA. Core Needle and Open Surgical Biopsy for Diagnosis of Breast Lesions: An Update to the 2009 Report. Rockville, MD: Agency for Healthcare Research and Quality (US); 2014:14-EHC040-EF.

24. Alkuwari E, Auger M. Accuracy of fine-needle aspiration cytology of axillary lymph nodes in breast cancer patients: a study of 115 cases with cytologic-histologic correlation. Cancer 2008;114(2):89-93.

25. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 2013;14(7):609-618.

26. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA 2013;310(14):1455-1461.

27. Kranick JA, Schaefer C, Rowell S, et al. Is pregnancy after breast cancer safe? Breast J 2010;16(4):404-411.

28. Peate M, Meiser B, Hickey M, Friedlander M. The fertility-related concerns, needs and preferences of younger women with breast cancer: a systematic review. Breast Cancer Res Treat 2009;116(2):215-223.

29. Lee S, Ozkavukcu S, Heytens E, Moy F, Oktay K. Value of early referral to fertility preservation in young women with breast cancer. J Clin Oncol 2010;28(31):4683-4686.

30. Moore HC, Unger JM, Phillips KA, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med 2015;372(10):923-932.

31. Knobf MT, Major-Campos M, Chagpar A, Seigerman A, McCorkle R. Promoting quality breast cancer care: psychosocial distress screening. Palliat Support Care 2014;12(1):75-80.

32. Holland JC, Jacobsen PB, Andersen B, et al. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Distress Management, v.1.2015. http://www.nccn.org/professionals/physician_gls/pdf/distress.pdf. Accessed May 12, 2015.

33. DeMichele A, Yee D, Berry DA, et al. The neoadjuvant model is still the future for drug development in breast cancer. Clin Cancer Res 2015 Feb 24. [Epub ahead of print]

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Current Treatment Options for Neoadjuvant Therapy in Breast CancerHope S. Rugo, MD

Optimal neoadjuvant therapy for patients with breast cancer is based on clinical and biologic factors, including patient preference for breast conservation, hormone receptor (HR) status, HER2 status, clinical stage, and nodal status. Traditional indications for neoadjuvant therapy include N2 stage, fixed or matted lymph node on ipsilateral side, and making the clinical staging at least stage IIIA or above.1 Patients with stage IIIB disease with tumors invading the chest wall, skin, or both, or with inflammatory breast cancer are also good candidates for neoadjuvant therapy. Neoadjuvant therapy also should be considered for women with clinical stage T1c, IIA, and IIB tumors with a larger tumor size who wish to have breast-conserving surgery.2 Neoadjuvant therapy is most appropriate for patients who are more likely to have a complete or near complete pathologic response (pCR), such as patients with HER2-positive, triple-negative, or highly proliferative HR-positive breast cancer.3

The primary goal of neoadjuvant therapy is to down-stage disease, allowing more patients to be candidates for breast-conserving surgery rather than mastectomy.4 Additional goals include the ability to test the efficacy of systemic and targeted therapy and to develop a more accurate individualized prognosis based on response and predictive biomarkers. In the future, we hope to be able to use variations of neoadjuvant treatment to improve disease-free survival (DSF), and that information obtained from response to novel therapeutics administered in the neoadjuvant setting will lead to more successful definitive studies.5

This monograph briefly reviews current evidence on the safety and efficacy of approved and emerging regimens used for the treatment of breast cancer in the neoadjuvant setting.

Prognosis: the role of pathologic complete response and Ki-67

In order to discuss neoadjuvant therapy, it is important to first define clinically significant endpoints. Earlier trials defined pCR as the absence of invasive cancer in breast alone; subsequently, the prognostic importance of residual disease in axillary nodes has been recognized. This has changed the universal definition of pCR to the absence of invasive disease in breast and axillary lymph nodes. The residual cancer burden score developed by Symmans et al6 attempted to further define prognosis by categorizing the extent of residual disease using both location and cellularity, although it has not been widely adopted. Recently, an international group published a consensus for pathologic characterization of residual disease in patients receiving neoadjuvant therapy for the purpose of standardizing clinical trial endpoints.7

Recently, the US Food and Drug Administration endorsed the use of pCR as an endpoint in neoadjuvant clinical trials. A meta-analysis was subsequently performed to evaluate the impact of improved pCR on DSF.8 Data from 12 international trials involving almost 12,000 patients were included in

the analysis. Pathologic complete response in both breast and node was associated with event-free survival, with the strongest association seen in patients with triple-negative or HER2-positive/HR-negative disease. Increases in pCR rates within trials did not correlate with improved event-free survival, raising a question about the use of pCR as a surrogate marker for improved event-free or overall survival (OS). However, in the majority of these trials, patients with indolent HR-positive disease were included along with those with more aggressive subtypes (with the exception of the trials evaluating trastuzumab for HER2-positive disease). It may be that newer clinical trials focusing on specific biologic subsets of breast cancer will identify an association between incremental benefits in pCR and disease outcome. Clearly, patients with strongly HR-positive, slowly proliferative cancers are unlikely to benefit from neoadjuvant chemotherapy if the goal is to reduce tumor size. These patients should be excluded from neoadjvuant chemotherapy trials and considered for other approaches such as neoadjuvant hormone therapy or up-front surgery.

Markers that may also have a predictive value in patients treated with preoperative therapy include markers of proliferation such as Ki-67.9 The presence of elevated Ki-67 before neoadjuvant therapy has been found to predict response to chemotherapy in locally advanced breast cancer. Ki-67 is the most commonly used and extensively studied biomarker of treatment activity and residual risk in neoadjuvant trials involving endocrine therapy, new biological therapies, and chemotherapy. It is increasingly being used as a primary endpoint for trials of new therapies in HR-positive disease, particularly with targeted agents added to endocrine therapy, although it is not widely used in the clinic. The ongoing POETIC trial, involving more than 4,000 postmenopausal, HR-positive patients randomly assigned to receive 2 weeks of presurgical treatment with an aromatase inhibitor or no further treatment, is the largest trial conducted and is assessing the clinical utility of reduction in Ki-67 as a predictor of long-term outcome. The ongoing ALTERNATE trial, in which Ki-67 level at 4 weeks following the initiation of neoadjuvant endocrine therapy is used to select patients who will continue anastrozole or fulvestrant versus those who should switch to chemotherapy (defined by persistent elevation in Ki-67), will provide important insight on this topic.

The presence of infiltrating lymphocytes has been associated with response to neoadjuvant chemotherapy.10 It is not yet clear how this information will be utilized to improve treatment response, but this will be studied in upcoming trials testing immune checkpoint blockade and immunological biomarkers such as extent of lymphocytic infiltration in tumor tissue

Neoadjuvant therapy in patients with HER2-positive diseaseTrastuzumab

In women with HER2-positive invasive breast cancer, the addition of trastuzumab to chemotherapy in the preoperative setting has been associated with an increase in pCR rates.

Current Treatment Options for Neoadjuvant Therapy in Breast Cancer

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Buzdar et al11 examined the addition of neoadjuvant weekly trastuzumab to paclitxel followed by chemotherapy with FEC (fluorouracil, epirubicin, and cyclophosphamide). After 34 patients had completed therapy, the trial was stopped early due to the superiority of adding trastuzumab to chemotherapy, which was associated with an increase in the pCR rate from 26% to 67%. The safety of this approach was not established, although no clinical congestive heart failure was observed.

The phase 3 NOAH trial compared 1 year of treatment with trastuzumab (administered as neoadjuvant and adjuvant treatment) with no trastuzumab, in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil.12 A parallel cohort of patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer: the 3-year event-free survival was 71% with trastuzumab versus 56% without. In a recent 5-year update, the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease (58% vs. 43%).13 In addition, event-free survival was strongly associated with pathological complete response in patients given trastuzumab. These and other trials have established trastuzumab-containing regimens as the gold standard of neoadjuvant therapy for HER2-positive disease.

LapatinibFour trials have evaluated the dual epidermal growth

factor receptor (EGFR) and HER2 inhibitor lapatinib in the neoadjuvant setting. First, the GeparQuinto trial studied 620 women with HER2-positive breast cancer and compared the addition of trastuzumab versus lapatinib to standard preoperative systemic chemotherapy.14 Pathologic complete response was achieved in 30% of patients who received trastuzumab plus chemotherapy, compared to 23% in patients who received lapatinib plus chemotherapy. Edema and dyspnea occurred more frequently in the trastuzumab group, whereas diarrhea and skin rash occurred significantly more frequently in the lapatinib group. The authors concluded that unless long-term outcome data demonstrate different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy.

The NeoALTTO trial evaluated the concurrent use of trastuzumab and lapatinib.15 The study randomly assigned 455 patients with HER2-positive primary invasive breast cancer with tumor size greater than 2 cm to receive lapatinib plus paclitaxel, trastuzumab plus paclitaxel, or a combination of lapatinib and trastuzumab plus paclitaxel. The results demonstrated that the pCR rate was significantly higher in the group given lapatinib and trastuzumab (51.3%) compared to 29.5% in the trastuzumab arm and 24.7% in the lapatinib arm. Although the difference in pCR rate between the lapatinib plus trastuzumab arm was statistically significant, recent long-

term results from the NeoALTTO trial failed to demonstrate a significant difference between event-free or OS between treatment groups; these results are in concert with the adjuvant ALTTO trial data.16 However, the study confirmed that patients who achieved pCR after neoadjuvant anti-HER2 therapy had longer event-free and OS than do patients without pCR.

In the phase 3 CALGB 40601 trial, patients were randomly assigned to receive trastuzumab/paclitaxel, trastuzumab/paclitaxel plus lapatinib, or lapatinib/paclitaxel, all administered for 16 weeks prior to surgery.17 The rates of pCR in the breast were 56% for the three-drug combination and 46% for trastuzumab/paclitaxel, a difference that was not statistically significant. Patients with HR-negative tumors had higher pCR rates after dual blockade (77% vs. 55%), but the differences were modest in the HR-positive tumors (42% vs. 39%). In either group, the improvement with the addition of lapatinib was not significant and the incidence of Grade 3/4 toxicities were higher. Thus, the use of two HER2-directed agents was no more effective than trastuzumab alone in producing pathologic complete responses.

Finally, the NSABP B-41 trial studied the effect of substituting neoadjuvant lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer.18 Breast pCR was noted in 52.5% of patients in the trastuzumab group, 53.2% patients in the lapatinib group, and 62.0% patients in the combination group. Thus, combined HER2-targeted therapy did not produce a significantly higher pCR percentage than single-agent HER2-directed therapy, a result consistent with other studies. Collectively, these trials demonstrate that the administration of lapatinib in HER2-positive breast cancer in the neoadjuvant setting only marginally improves the probability of achieving a higher pCR rate, and is associated with a significantly increased risk of toxicity.19

PertuzumabPertuzumab is a recombinant, humanized monoclonal

antibody that inhibits the ligand-dependent dimerization of HER2 and its downstream signaling. Pertuzumab and trastuzumab bind to different epitopes of HER2 receptor, have complementary mechanisms of action, and provide a greater overall antitumor effect when administered together than either alone.20 The FDA recently granted accelerated approval for pertuzumab in combination with trastuzumab and docetaxel as neoadjuvant treatment for patients with HER2-positive breast cancer based on the results of two phase II trials.

The NeoSphere trial12 evaluated 417 patients with HER2-positive breast cancer who were randomly assigned to receive one of three treatments: (1) trastuzumab plus docetaxel, (2) pertuzumab and trastuzumab plus docetaxel, or (3) pertuzumab and trastuzumab or pertuzumab plus docetaxel. The trial demonstrated that 46% of patients who received pertuzumab plus trastuzumab and docetaxel achieved a

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pCR compared to only 29% of patients who received the trastuzumab plus docetaxel regimen, without substantial differences in toxicity. In a recent update to the NeoSphere trial, longer-term outcomes were measured: 3-year survival rates were significantly improved in the pertuzumab-containing arms (DFS: 92% vs. 85%, progression-free survival: 90% vs. 86%).21

Cardiac adverse events are a cause of concern when treating patients with HER2-targeted agents in combination with chemotherapy. The TRYPHAENA study was a phase 2, randomized, multicenter trial designed to evaluate the safety trastuzumab and pertuzumab in combination with anthracycline- or carboplatin-based neoadjuvant chemotherapy.22 A total of 225 patients with HER2-positive breast cancer (locally advanced, inflammatory, early-stage) were enrolled and randomly assigned to receive six cycles of neoadjuvant therapy with 5-fluorouracil, epirubicin, cyclophosphamide (FEC) plus trastuzumab and pertuzumab followed by docetaxel, trastuzumab, and pertuzumab; or FEC followed by docetaxel, trastuzumab, and pertuzumab; or docetaxel, carboplatin, and trastuzumab plus pertuzumab. The reported pCR rates ranged from 57% to 66%. The adverse events reported in the trial were consistent with known effects from the three agents and low rates of left ventricular systolic dysfunction were reported (3.9% to 5.6%).

The combined results of the NeoSphere and Trypheana trials led to accelerated approval of pertuzumab in combination with trastuzumab-based chemotherapy as neoadjuvant therapy for HER2-positive breast cancer, using the new definitions established by the FDA. Final approval is pending the results of the adjuvant Aphinity trial that adds pertuzumab or placebo to standard adjuvant chemotherapy for HER2-positive early-stage breast cancer

T-DM1Ado-trastuzumab emtansine (T-DM1) is an antibody-

drug conjugate in which trastuzumab is stably linked to the microtubule inhibitor maytansine (DM1). It is currently approved for HER2-positive metastatic breast cancer and is being tested in the neoadjuvant setting. In the recent interim analysis of the phase 2 ADAPT trial, patients with HER2-positive and HR-positive breast cancer were randomly assigned to receive neoadjuvant T-DM1 with or without endocrine therapy or trastuzumab plus endocrine therapy.23 Treatment was administered for 4 cycles followed by surgery and 1 year of standard adjuvant chemotherapy plus trastuzumab. In the T-DM1 alone arm, the pCR rate was 40.5%; in the T-DM1 plus endocrine therapy arm, the pCR rate was 45.8%; and in the trastuzumab plus endocrine therapy arm, the pCR rate was 6.7%. These pCR rates compare favorably with those seen in the NSABP B-41 and GeparSepto trials. In premenopausal patients, single-agent T-DM1 demonstrated a 27% pCR rate versus 60% in those who were postmenopausal. The most common all-grade adverse events with single-agent T-DM1 were thrombocytopenia (30%), aspartate aminotransferase increase (19%), alanine aminotransferase increase (22%), and infections and infestations (11%). Final results of this trial are pending. T-DM1 is also being evaluated in two additional

trials: (1) the KRISTINE trial (NCT02131064), in which patients are randomly assigned to receive T-DM1 with pertuzumab compared with the TCHP regimen (docetaxel, carboplatin, trastuzumab, pertuzumab), and (2) the phase 3 KATHERINE trial (NCT01772472), in which patients with residual disease after neoadjuvant trastuzumab are randomly assigned to continuation of trastuzumab or to T-DM1.

Emerging novel agentsTo overcome resistance to HER2 blockade, several new

agents that inhibit HER2 itself or its interacting molecules, are in clinical investigation. Ertumaxomab, for example, is a trifunctional, bispecific monoclonal antibody targeting HER2 and CD3. Neratinib, in contrast, is a tyrosine kinase inhibitor blocking HER1 and HER2 irreversibly. Other approaches are tumor vaccines against HER2, a dual HER2 and insulin-like growth factor-1 receptor blockade, and inhibition of heat-shock protein-90.

Neoadjuvant therapy for patients with hormone-receptor (HR) positive, HER2-negative disease

Neoadjuvant hormonal therapy is considered to be a suitable option for patients with HR-positive disease who are unfit for chemotherapy or surgery, and is increasingly being utilized to achieve tumor downsizing before surgery in postmenopausal women.24 However, the broad use of endocrine therapy as a tool in the neoadjuvant setting is limited due to the slow response rate of these tumors in general, requiring long duration of therapy and risking the benefit of early surgical intervention.1,25 Treatment with neoadjuvant endocrine therapy in patients with hormone-receptor (HR) positive breast cancer is thus usually reserved for postmenopausal women with slowly proliferative tumors that are unlikely to respond to chemotherapy (although a small number of trials involving premenopausal women have been conducted, including the phase 3 STAGE trial of neoadjuvant anastrozole versus tamoxifen.26

Aromatase inhibitors (AIs) are generally preferred over tamoxifen in this setting. The IMPaCT trial evaluated the effect of neoadjuvant anastrozole versus tamoxifen in postmenopausal women with HR-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer.27 The trial demonstrated no significant difference in objective response between patients receiving tamoxifen, anastrozole, or the combination. However, 46% of patients received breast-conserving surgery after anastrozole compared with 22% of patients after tamoxifen. In addition, patients treated with anastrozole had a significant suppression of Ki-67 level at both 2 and 12 weeks compared with tamoxifen-treated patients, providing evidence for the utility of Ki-67 as a prognostic biomarker. Ellis et al28 studied neoadjuvant letrozole versus tamoxifen in postmenopausal patients with ER-positive and/or PR-positive primary breast cancer ineligible for breast-conserving surgery. Data demonstrated that letrozole improved response rates (60% vs. 41%) and the rate of successful breast conserving surgeries (48% vs. 36%) compared to the tamoxifen-treated group.

6


Other agents such as lapatinib and the mTOR inhibitor everolimus have been combined with AIs in the neoadjuvant setting. For example, in a phase 2 trial, postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole and either everolimus or placebo.29 Response rate in the everolimus arm was higher than that with letrozole alone (68.1% vs. 59.1%). In addition, an antiproliferative response, as defined by a reduction in Ki67 expression, occurred in 57% of patients in the everolimus arm and in 30% of patients in the placebo arm. Grade 3/4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo. In a randomized phase 2b trial of postmenopausal women with HR-positive, HER2-negative stage II to IIIA primary breast cancer, letrozole plus lapatinib or placebo was evaluated.30 In unselected patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on biomarkers such as Ki-67 and pAKT. In patients with a mutation in PIK3CA exon 9 or 20, however, the objective response rate was 93% versus 63% in patients with wild-type PIK3CA.

Additional studies have evaluated combining chemotherapy agents or changing chemotherapy based on poor response but have not demonstrated a significant impact on either pCR rates or long-term outcomes in patients with HER2-negative breast cancer.31-33 Similarly, the addition of bevacizumab to standard neoadjuvant chemotherapy in the GeparQuinto and and NSABP B-40 trials improved pCR in some subsets,34,35 but did not improve OS or event-free survival.36 The addition of everolimus also had no impact on outcome.36 Ongoing studies are evaluating PI3K inhibitors and inhibitors of cyclin dependent kinase inhibitor 4/6 in combination with aromatase inhibitors.

Neoadjuvant therapy for patients with triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous disease that represents a challenge clinically due to a lack of response to hormonal and HER2-targeted agents coupled with an aggressive disease course. It accounts for 10-15% of breast cancer cases and most commonly occurs in younger women, African Americans, and in BRCA gene-mutated populations.

Despite having a poorer overall prognosis, patients with nonmetastatic TNBC treated with neoadjuvant chemotherapy seem to have a better response than patients with HR-positive breast cancer. In one trial of 1,118 patients with stage I to stage III breast cancer treated with standard neoadjuvant chemotherapy regimens, pCR rates of 22% were seen in patients with TNBC versus 11% in non-TNBC.37 However, 3-year PFS, OS, and post-recurrence survival were lower in patients with TNBC. Patients with pCR clearly had better outcome; the differences in outcome were due to the impact of HER2-targeted and hormone therapies in subsets responsive to those therapies. Dose-dense chemotherapy regimens seems to benefit patients with TNBC. A

retrospective study (WSG AM-01) evaluated a dose-dense regimen of four cycles of epirubicin and cyclophosphamide followed by three cycles of cyclophosphamide, methotrexate, fluorouracil (CMF) compared with high-dose chemotherapy and peripheral stem cell support in patients with high-risk breast cancer.38 Among patients with TNBC, OS was 76% for those receiving high-dose chemotherapy compared with 61% in the dose-dense arm. Toxicity, treatment-related mortality, and heterogeneous results has led to the discontinuation of high-dose chemotherapy regimens for the treatment of breast cancer.

Two recent randomized trials have assessed the impact of carboplatin on pCR rates in TNBC, based on data suggesting that a subset of TNBCs have a defect in DNA repair. The randomized phase 2 GeparSixto study aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.36 Patients were treated for 18 weeks with a nonstandard regimen including paclitaxel and nonpegylated liposomal doxorubicin. Patients with TNBC received simultaneous bevacizumab and patients with HER2-positive disease received simultaneous trastuzumab and lapatinib; both groups were then randomized to receive carboplatin or not. The addition of carboplatin resulted in improvement in pCR in patients with TNBC, with 43.7% of those in the carboplatin group achieving a pathological complete response compared with 36.9% who did not receive carboplatin. Hematological and nonhematological toxic effects were significantly more common in the carboplatin group.

The CALBG 40603 (ALLIANCE) trial also studied the impact of both carboplatin and bevacizumab in patients with TNBC, but used a standard chemotherapy backbone.39 Patients with stage II to stage III TNBC were treated with weekly paclitaxel for 12 weeks with or without carboplatin and with or without bevacizumab, with all arms receiving subsequent doxorubicin plus cyclophosphamide. The addition of either carboplatin (60% vs. 44%) or bevacizumab (59% vs. 48%) significantly increased pCR, with the greatest impact seen with the addition of carboplatin. Grade 3/4 neutropenia and thrombocytopenia were more common with carboplatin, and treatment with bevacizumab was associated with more hypertension, infection, thromboembolic events, bleeding, and postoperative complications. The critical question is now whether these improvements in pCR will translate into improvements in DFS and OS. Generally neoadjuvant trials are not powered to detect survival differences, but these endpoints are being carefully followed and will be reported in the near future.

Other studies have evaluated the combination of novel agents with neoadjuvant chemotherapy, with generally disappointing results. The GeparQuinto study demonstrated that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increased pCR rates overall and specifically in patients with triple-negative breast cancer.35,40 However, there was no difference in either DFS or OS in those patients receiving bevacizumab compared with

7


patients receiving chemotherapy alone. In contrast to the pCR results, long-term data do not support the use of neoadjuvant bevacizumab in addition to an anthracycline–taxane-based chemotherapy. An additional study evaluated the addition of neoadjuvant everolimus in non-early responding patients and saw no difference in any endpoint, including pCR.35

Many other trials are evaluating novel agents for the neoadjuvant treatment of TNBC, including the addition of PI3K pathway inhibitors, mTOR inhibitors, combination PI3K/mTOR inhibitors, AKT inhibitors, epothilones, EGFR inhibitors, and PARP inhibitors to standard adjuvant chemotherapy. The I-SPY-2 trial uses an adaptive design based on biomarker subtypes to evaluate multiple novel agents in the neoadjuvant setting.41 The goal is to identify and “graduate” regimens that have at least an 85% Bayesian predictive probability of success in future biomarker-linked phase 3 neoadjuvant trials. In the study of 71 patients, the PARP inhibitor veliparib plus carboplatin, added to standard neoadjuvant chemotherapy, produced an estimated pCR rate of 52% compared to 26% in the control arm, and thus the novel agent “graduated.” This combination is now being tested in the international phase III Brightness trial, which randomly assigns women with early stage TNBC to receive neoadjuvant therapy with paclitaxel, paclitaxel and carboplatin, or paclitaxel, carboplatin and veliparib. All three arms receive doxorubicin

and cyclophosphamide after paclitaxel, and then proceed to surgery. The primary endpoint of this trial is pCR, with secondary endpoints of DFS and OS. Additionally, neratinib, an oral tyrosine kinase inhibitor of HER1, HER2, and HER4, demonstrated an improvement in estimated pCR rates in patients with HER2-positive/HR-negative disease .42 A phase III trial is planned.

ConclusionNeoadjuvant treatment is indicated for patients with large

tumor size, positive axillary nodes, inflammatory disease, or for patients who wish to pursue breast-conserving surgery. Rates of pCR are higher in patients with HER2-positive, triple-negative, or highly proliferative hormone responsive disease. It is also increasingly recognized as an important strategy in biomarker and novel therapy evaluation. These studies will likely result in more rapid registration trials focused on the patients and tumors most likely to benefit from the specific novel therapeutic. Neoadjuvant treatment with chemotherapy plus trastuzumab or pertuzumab is the standard care for women with locally advanced, HER2-positive breast cancer. The addition of carboplatin or cisplatin to standard neoadjuvant chemotherapy in patients with TNBC appears to increase pCR rates; however, it also increases toxicity and is not yet considered the standard of care in this setting due to the lack of evidence suggesting long-term benefit.

References01. Miller E, Lee HJ, Lulla A, et al. Current treatment of early breast

cancer: adjuvant and neoadjuvant therapy. F1000Res 2014;3:198.02. Onitilo AA, Onesti JK, Single RM, et al. Utilization of neoadjuvant

chemotherapy varies in the treatment of women with invasive breast cancer. PLoS ONE 2013;8(12):e84535.

03. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30(15):1796-1804.

04. Amoroso V, Generali D, Buchholz T, et al. International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013). J Natl Cancer Inst Monogr 2015;2015(51):90-96.

05. Ye D, Haddad T, Albain K, et al. Adaptive trials in the neoadjuvant setting: a model to safely tailor care while accelerating drug development. J Clin Oncol 2012;30(36):4584-4586.

06. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28):4414-4422.

07. Bossuyt V, Provenzano E, Symmans WF, et al. Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann Oncol 2015;26(7):1280-1291.

08. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384(9938):164-172.

09. Klintman M, Dowsett M. Early surrogate markers of treatment activity: where are we now? J Natl Cancer Inst Monogr 2015;2015(51):24-28.

10. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015;26(2):259-271.

11. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23(16):3676-3685.

12. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(1):25-32.

13. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014;15(6):640-647.

14. Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 2012;13(2):135-144.

15. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379(9816):633-640.

16. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 2014;15(10):1137-1146.

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17. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol 2013; 31(15 suppl):abstr 500).

18. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14(12):1183-1192.

19. Sun J, Chen C, Yao X, et al. Lapatinib combined with neoadjuvant paclitaxel-trastuzumab-based chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis of randomized controlled trials. Oncol Lett 2015;9(3):1351-1358.

20. Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 2009;69(24):9330-9336.

21. Gianni L, Pienkowski T, Im YH, et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol 2015;33(suppl):abstr 505.

22. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24(9):2278-2284.

23. Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol 2015;33(suppl):abstr 506.

24. Charehbili A, Fontein DB, Kroep JR, et al. Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: a systematic review. Cancer Treat Rev 2014;40(1):86-92.

25. Colleoni M, Montagna E. Neoadjuvant therapy for ER-positive breast cancers. Ann Oncol 2012;23(Suppl 10):243-248.

26. Masuda N, Sagara Y, Kinoshita T, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol 2012;13(4):345-352.

27. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23(22):5108-5116.

28. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19(18):3808-3816.

29. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009;27(16):2630-2637.

30. Guarneri V, Generali DG, Frassoldati A, et al. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 2014;32(10):1050-1057.

31. Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002;20(6):1456-1466.

32. Earl HM, Vallier AL, Hiller L, et al. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol 2014;15(2):201-212.

33. von Minckwitz G, Blohmer JU, Costa SD, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 2013;31(29):3623-3630.

34. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012;366(4):299-309.

35. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012;366(4):310-320.

36. von Minckwitz G, Loibl S, Untch M, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto). Ann Oncol 2014;25(12):2363-2372.40. Gerber B, Loibl S, Eidtmann H, et al, Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol 2013;24(12):2978-2984.

37. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26(8):1275-1281.

38. Gluz 1, Nitz UA, Harbeck N, et al; West German Study Group. Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial. Ann Oncol 2008;19(5):861-870.

39. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015;33(1):13-21.

35. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012;366(4):310-320.

41. Rugo HS, Olopade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY 2 trial. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013.

42. Park JW, Liu MC, Yee D, et al. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: efficacy results from the I-SPY 2 TRIAL. Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. Abstract CT227.

9

Preoperative Systemic Therapy Guidelines and Relevant Quality MeasuresWilliam J. Gradishar, MD, FACP

Early-stage breast cancer represents a potentially curable disease, with surgery as a primary mode of treatment and neoadjuvant therapy an option for patients with defined clinical characteristics.1-3 Clinical practice guidelines recommend specific neoadjuvant therapies and provide clear criteria for considering their use in patients with stage II-III breast cancer.1 Although there is no defined ideal benchmark for referral or consultation rates in the United States, both referral to and consultation with an oncologist have been identified as quality care metrics for patients with resected (or resectable) disease treated in Canada.2 Despite the existence of clinical practice guidelines in the United States, rates of utilization of neoadjuvant therapy have been reported as inconsistent and as low as 3.8% of all patients with breast cancer, strongly suggesting that preoperative systemic therapy is being underutilized.4 This monograph reviews current clinical practice guidelines and quality measures for neoadjuvant therapy in early-stage breast cancer in the United States and discusses issues that lead to noncompliance.

Clinical practice guidelinesThe NCCN Clinical Practice Guidelines for the management

of breast cancer were developed more than 15 years ago. These practice guidelines are regularly reviewed and revised by the multidisciplinary Breast Cancer Panel of the NCCN.5 The guidelines provide synthesis of the best

available evidence and the recommended specific treatment algorithms for care of stage I-IV breast cancer.1 Neoadjuvant therapy is recommended in cases with confirmed invasive disease. It is a treatment recommendation for patients with large tumors classified as clinical stage IIA, stage IIB, or T3N1M0 who meet all criteria for breast-conserving therapy except for tumor size, and who express a preference to undergo breast-conserving therapy.1 Full details of the NCCN recommendations are described in Table 1.

Evidence-based clinical practice guidelines also are developed by the American Society of Radiology, the American Society of Clinical Oncology (ASCO), and other oncology professional organizations. ASCO endorsed the use of trastuzumab in 2014 for use in patients with primary breast cancer that is HER2-positive, node-positive, or node-negative, with tumors greater than 1 cm in size, and who are receiving or have received (neo)adjuvant chemotherapy.6 No other neoadjuvant practice recommendations are specifically outlined by these professional organizations.

Quality metricsThe American Medical Association (AMA)-convened

Physician Consortium for Performance Improvement (PCPI) is a national, physician-led program dedicated to enhancing quality care and patient safety.7 The PCPI has developed evidence-based performance measures that are clinically relevant and can be used for quality improvement programs. ASCO established the Task Force on Quality of Cancer Care in 1989 in response to the Institute of Medicine’s report Ensuring Quality Cancer Care.8 The National Initiative on Cancer Care Quality (NICCQ) task force found that,

Preoperative Systemic Therapy Guidelines and Relevant Quality Measures

Table 1. NCCN neoadjuvant therapy algorithm

Adapted with permission from the National Comprehensive Cancer Center Network.1

Clinical Stage

Stage IIA T2, N0, M0

Stage IIB T2, N1, M0 T3, N0, M0

Stage IIIA T3, N1, M0

and

Fulfills criteria for breast-conserving surgery except for tumor size

Workup

• History and physical exam

• CBC, platelets

• Liver function tests and alkaline phosphatase

• Diagnostic bilateral mammogram; ultrasound as necessary

• Pathology review

• Determination of tumor ER/PR status and HER2 status

• Genetic counseling if patient is high risk for hereditary breast cancer

• Breast MRI (optional), with special consideration for mammographically occult tumors

• Fertility counseling if premenopausal

Consider systemic staging (particularly if signs and symptoms are present):

• Chest diagnostic CT

• Abdominal ± pelvic diagnostic CT or MRI

• Bone scan or sodium fluoride PET/CT (category 2B)

• FDG PET/CT (optional, category 2B)

See Preoperative Systemic Therapy Breast and Axillary Evaluation (BINV-11)

10

on average, patients with breast cancer received 86% of generally recommended care, based on 36 quality care measures examined at that time.9 In response to the NICCQ task force recommendations, ASCO developed a formal process of quality monitoring called the Quality Oncology Practice Initiative (QOPI) in 2004.10 This initiative sought to collaborate with practicing oncologists and quality experts to improve the quality of care that oncology patients receive.10 These experts have identified measures that are derived from clinical practice guidelines or published standards adapted from the NICCQ, ASCO, and NCCN quality measures, and the American Society for Therapeutic Radiology and Oncology and AMA PCPI oncology measures. Quality measures related to breast cancer treatment in the neoadjuvant/adjuvant settings are described in Table 2.

Deviation from guidelinesFew contraindications to breast-conserving surgery exist

for newly diagnosed breast cancer patients, and the use of systemic therapy initially is the standard of care for patients with locally advanced or inflammatory cancer.1,12 However, clinical and patient-driven deviations from these guidelines are poorly understood. One study using multi-institutional data from nearly 3,000 women documented that only 3.8% of breast cancer patients received neoadjuvant chemotherapy.13 The variable recommendations for neoadjuvant therapy among providers suggest that preoperative systemic therapy may be vastly underutilized in eligible patients desiring breast conservation, and that provider and institutional factors, such as provider knowledge and institutionally based care coordination networks, likely play large roles in influencing treatment patterns. Others suggest that barriers such as age, the presence of microcalcifications, or microinvasive tumor pathology lead to deviation from a guideline that is broad in scope and unable to include such granular clinical decision making.12,13 Studies in Canada identified factors that cause

deviations from neoadjuvant treatment recommendations, including geographic location, comorbidities, patient age, and prevailing wait times. While these barriers are valid only within the health system studied, they suggest areas for further investigation.

Other barriers involving the patient and the decision-making process have been identified. In a study of 322 patients who underwent unilateral or bilateral mastectomy for breast cancer during 2006 to 2010, 44% of women younger than age 50 years of age and 41% of women older than 50 years of age who were given the option of breast-conserving therapy chose mastectomy instead.15 In addition, their reasons for doing so remained the same for both age groups: lower recurrence risk and improved survival. Patient preferences are an important element in the presurgical evaluation for neoadjuvant therapy.13 Some suggest a quality metric for patient satisfaction with their surgical choice, while others have evaluated decision dissonance—the score that measures the extent to which patient ratings of goals ran counter to the treatment received.16 The use of such a metric would further inform surgeons of the role of patient preference in decision making and the impact of decision-making tools and techniques in the process.

The variable use of neoadjuvant therapy among providers and their patients suggests that preoperative systemic therapy may be underutilized in eligible patients desiring breast conservation, and that provider and institutional factors, such as provider knowledge and institutionally based care coordination networks, likely play large roles in influencing treatment patterns. Adherence to clinical practice guidelines that provide evidence for this approach and employ decision-making tools and patient-physician communication methods may increase the use of this breast-conserving therapy option.

Metric QOPI National quality forumTrastuzumab (adjuvant/neoadjuvant) recommended for patients with AJCC stage I (T1c) to III HER2/neu-positive breast cancer

55, 56 Endorsed: 1858, 1857

Trastuzumab is not recommended when HER2/neu is negative or undocumented (inverse of 56)

56a Endorsed: 1857

Combination chemotherapy recommended and received within 4 months of diagnosis by women younger than 70 years with AJCC stage I (T1c) to III ER/PR-negative breast cancer

52, 53 Endorsed: 0559

Test for HER2/neu overexpression or gene amplification 53 Endorsed: 1878

Table 2. Quality metrics for neoadjuvant breast cancer therapy

AJCC indicates American Joint Committee on Cancer; QOPI, Quality Oncology Practice Initiative. Adapted with permission from ASCO.11


11


References01. National Comprehensive Cancer Center Network. NCCN Clinical

Practice Guidelines ([NCCN Guidelines®]) in Oncology: Breast Cancer, v2.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 19, 2015.

02. Urquhart R, Kendell C, Sargeant J, et al. How do surgeons decide to refer patients for adjuvant cancer treatment? Protocol for a qualitative study. Implement Sci 2012;7:102.

03. Schmidt M. Chemotherapy in early breast cancer: when, how and which one? Breast Care (Basel) 2014;9(3):154-160.

04. Onitilo AA, Onesti JK, Single RM, et al. Utilization of neoadjuvant chemotherapy varies in the treatment of women with invasive breast cancer. PLoS One 2013;8(12):e84535.

05. Carlson RW, Allred DC, Anderson BO, et al. Invasive breast cancer. J Natl Compr Canc Netw 2011;9(2):136-222.

06. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014;32(19):2078-2099.

07. American Medical Association. Physician Consortium for Performance Improvement. http://www.ama-assn.org/ama/pub/physician-resources/physician-consortium-performance-improvement.page? Accessed March 19, 2015.

08. National Cancer Policy Board Institute of Medicine and Commission on Life Sciences. Hewitt M, Simone JV, eds. Ensuring Quality Cancer Care. Washington, DC: National Academy Press; 2015.

09. American Society of Clinical Oncology. National Initiative on Cancer Care Quality. http://www.asco.org/quality-guidelines/national-initiative-cancer-care-quality-niccq. Accessed March 20, 2015.

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10. Neuss MN, Desch CE, McNiff KK, et al. A process for measuring the quality of cancer care: the Quality Oncology Practice Initiative. J Clin Oncol 2005;23(25):6233-6239.

11. American Society of Clinical Oncology. Quality of Oncology Practice Initiative. http://qopi.asco.org/program.html. Accessed March 19, 2015.

12. Sabel MS. Surgical considerations in early-stage breast cancer: lessons learned and future directions. Semin Radiat Oncol 2011;21(1):10-19.

13. Wockel A, Varga D, Kurzeder C, et al. Impact of guideline conformity on breast cancer therapy: results of a 13-year retrospective cohort study. Onkologie 2010;33(1-2):21-28.

14. Ong S, Watters JM, Grunfeld E, O’Rourke K. Predictors of referral for adjuvant therapy for colorectal cancer. Can J Surg 2005;48(3):225-229.

15. Fisher CS, Martin-Dunlap T, Ruppel MB, Gao F, Atkins J, Margenthaler JA. Fear of recurrence and perceived survival benefit are primary motivators for choosing mastectomy over breast-conservation therapy regardless of age. Ann Surg Oncol 2012;19(10):3246-3250.

16. Fowler FJ Jr, Gallagher PM, Drake KM, Sepucha KR. Decision dissonance: evaluating an approach to measuring the quality of surgical decision making. Jt Comm J Qual Patient Saf 2013;39(3):136-144.

Shared Decision Making: Physician and Patient BarriersJoanne Buzaglo, PhDIt is widely agreed that shared decision making (SDM) is the cornerstone of patient-centered care. Although SDM has been shown to improve patients’ understanding of treatment options, result in more conservative care choice, and lead to lower healthcare costs,1 its elements still are not well-understood and numerous misconceptions exist about the meaning of SDM.In short, SDM is best defined as when, “the physician and the patient make health-related decisions collaboratively, based on both the best available evidence and the patient’s values, beliefs, and preferences.”2 The word “collaboratively” is important; one misconception is that SDM is simply when physicians share a treatment decision with their patients and their patients simply follow the new treatment regimen. Some physicians are wary of SDM because they believe it means that patients are to make all decisions and physicians are to follow their patients’ desires without question, which could potentially result in harm to the patient. In medical practice, SDM depends on physicians and patients taking different roles in the clinical interaction and treatment decision. For example, it is the physician’s role to present all treatment options, provide patients with the best available evidence for the physician’s recommended treatment plan, help the patient weigh risks versus benefits, discuss uncertainties and treatment alternatives, present this information in as unbiased a way as possible, and verify the patient’s understanding. Patients also have several important roles and responsibilities if they are to be thoughtful participants in SDM. Patients must want to participate. They must clarify and voice their values, preferences, and goals relating to treatment. Finally, patients and physicians must listen carefully to each other, ask questions, and request additional information when necessary.3 Although SDM may seem an intuitive practice, several barriers exist from both physician and patient perspectives. Physicians, for example, may believe that SDM allows the patient to dictate to the physician regardless of the physician’s best judgment.4,5 Physicians may perceive SDM to take too much time and effort in an already too-short time frame.5 They may object to sharing all information about treatment options, particularly cost.6 A given physician’s institution or hospital may not provide infrastructure that supports patient engagement or SDM.4 Patient barriers to SDM include low health literacy and disinclination to engage in SDM.7,8

Breast cancer diagnosis and treatment can involve complex considerations from both the patient and physician perspectives.9 A number of the treatment options have similar outcome profiles in terms of survival or other quality of life measures; therefore, patient preference plays a critical role in SDM. Considerations may include whether to proceed with neoadjuvant or adjuvant chemotherapy, whether to have breast-conserving therapy or mastectomy, whether to undergo breast reconstruction and what type of reconstruction, etc. Neoadjuvant chemotherapy has made it possible for some women who may otherwise have been ineligible for breast conservation to successfully undergo treatment with breast conservation therapy10-15; yet use of neoadjuvant chemotherapy may be underutilized and varies across institutions.16 In a study of predictors of utilization of neoadjuvant therapy, younger age, preoperatively known positive nodal status, and increasing clinical tumor size were associated with greater uptake of neoadjuvant therapy16; however, these findings do not account for the potential patient–physician factors associated with SDM, such as patient level of knowledge about treatment options, barriers to engagement in decision making, and patient attitudes and concerns.

Shared Decision Making in Breast CancerWith respect to breast cancer, a number of studies have explored patient and physician factors associated with SDM. In a prospective study of patients’ choices for breast-conserving therapy versus mastectomy, patients’ perceptions about their surgeons’ preference and their concerns about breast loss and local tumor recurrence were the strongest predictors of treatment.17 The more concerned a patient was about losing her breast, the more likely she was to opt for breast conservation. Conversely, the more concerned a patient was about recurrence, the greater the likelihood she was to opt for mastectomy. Further, patients have been found to “freeze up” when speaking with their specialists, forgetting to ask questions and not fully absorbing the information that their doctor presents.18 This is particularly problematic because the majority of patients with breast cancer make decisions during their first visit after undergoing a biopsy.19,20 Moreover, studies have found that patients are not fully informed about their treatment options; 44% of patients being seen at an academic medical center did not know that breast cancer survival was equivalent for mastectomy versus lumpectomy plus radiation.21 This finding has been replicated with breast cancer survivors from other academic medical centers, among whom 51-58% were unaware of that critical fact.22-24 In addition, breast cancer survivors being seen at academic medical centers answered only 38% of questions correctly on reconstruction-specific knowledge and only 40% answered questions correctly about chemotherapy-specific knowledge related to options and outcomes.22 In a large study of over 900 breast cancer survivors, only 14% of respondents received information before the first specialist visit and at least 25% of respondents rated their satisfaction below 7 on a 10-point scale for decision-making, information, and questions asked and answered.25 Respondents reported the need for more assistance with obtaining information, asking questions, taking notes, and making audio recordings of visits. In a study that explored the concordance between physician perceptions and breast cancer patient preferences for SDM, approximately 85-90% of patients preferred an active or shared role in decision making while only approximately 40% of physicians are able to predict patient preference in treatment decision making.25 Patients with breast cancer who take a more active role in decision making report greater satisfaction with their care and no difference in amount of time they spend during the patient–physician encounter.19 In summary, while patients are influenced by the physician’s preferences, the majority of patients want to take a more active role in treatment decision making. Further efforts are needed to ensure that patients with breast cancer are more fully informed, receive greater encouragement to ask questions, take time to process their treatment options, and fully engage in a SDM process.

Shared Decision Making: Physician and Patient Barriers

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Shared Decision Making: Physician and Patient Barriers

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20. Belkora JK, Miller MF, Dougherty K, Gayer C, Golant M, Buzaglo JS. The need for decision and communication aids: a survey of breast cancer survivors. J Community Support Oncol 2015;13(3):104-112.

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22. Lee CN, Chang Y, Adimorah N, et al. Decision making about surgery for early-stage breast cancer. J Am Coll Surg 2012;214(1):1-10.

23. Hawley ST, Fagerlin A, Janz NK, Katz SJ. Racial/ethnic disparities in knowledge about risks and benefits of breast cancer treatment: does it matter where you go? Health Serv Res 2008;43(4):1366-1387.

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the neoadjuvant diagnostic workup hope s. rugo, md · undergo axillary lymph node sampling at the...

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