Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015

Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015 Sabrina Witherby, MD,*,† Tina Rizack, MD,* Bachir J. Sakr, MD,* Robert D. Legare, MD,* and William M. Sikov, MD, FACP* Standard management of early stage and advanced breast cancer has been improved over the past few years by knowledge gained about the biology of the disease, results from a number of eagerly anticipated clinical trials and the development of novel agents that offer our patients options for improved outcomes or reduced toxicity or both. This review highlights recent major developments affecting the systemic therapy of breast cancer, broken down by clinically relevant patient subgroups and disease stage, and briefly discusses some of the ongoing controversies in the treatment of breast cancer and promising therapies on the horizon. Semin Radiat Oncol 26:59-70 C 2016 Elsevier Inc. All rights reserved.

Introduction

A

lthough the number of breast cancer deaths in the United States has fallen over the past 15 years, it remains the most common serious cancer and second leading cause of cancer deaths among U.S. women. The past few years have seen a number of new drug approvals and the presentation of results from large, randomized studies that have changed treatment algorithms and offer hope of substantial improvements in outcomes in both early stage and advanced breast cancer. In this review, we discuss those advances and how they have affected the standard of care for many breast cancer patients, focusing on the 3 major subtypes—hormone receptor (HR)– positive/human epidermal growth factor receptor-2 (HER2)– negative, HER2-positive, and triple-negative.

*Program in Women's Oncology, Breast Health Center, Women and Infants Hospital of Rhode Island and Alpert Medical School of Brown University, Providence, RI. †Department of Medicine, Memorial Hospital of Rhode Island, Pawtucket, RI. Robert D. Legare, Sabrina Witherby, Tina Rizack, and Bachir J. Sakr have no conflict of interest. William M. Sikov is on the advisory board (uncompensated) of AbbVie and also received an honoraria (o$5000) from Celgene. Address reprint requests to William M. Sikov, MD, FACP, Breast Health Center, Women and Infants Hospital of Rhode Island, 101 Dudley St., Providence, RI 02906. E-mail: [email protected]

http://dx.doi.org/10.1016/j.semradonc.2015.09.005 1053-4296//& 2016 Elsevier Inc. All rights reserved.

Hormone Receptor–Positive/ HER2-Negative Breast Cancer Stage I-III HRþ/HER2 Disease Of patients diagnosed with breast cancer in the United States, 60%-70% have HR-positive and HER2-negative (HRþ/ HER2) cancers, the vast majority with stage I-II disease at presentation, especially among those whose cancers are detected by screening mammography (Fig. 1A). A major challenge in the management of these patients is to differentiate those who are at low risk for local or distant recurrence, in whom treatment should be limited and, ideally, have minimal effect on the patient's quality of life, from those at high risk for disease recurrence and death, in whom more intensive and potentially toxic treatments are warranted. Results from recent studies have addressed the duration of adjuvant endocrine therapy, assessed the role of ovarian function suppression (OFS) in premenopausal women and expanded the potential indications for neoadjuvant endocrine therapy. There has also been widespread adoption of the use of genomic assays to select patients in whom chemotherapy may, or may not, offer significant benefit over endocrine therapy alone. Although we have long been aware that more than half of the patients with these typically less-aggressive cancers who eventually recur will do so more than 5 years after initiation of adjuvant endocrine therapy, until fairly recently the benefit of extending that treatment beyond 5 years was uncertain. Studies such as National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 failed to demonstrate improved outcomes from extending tamoxifen from 5-10 years, though this 59

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60 B Stage IV

A Stage I-III

Stage I-IIA

Surgery

If path stage T1c or T2 N0 send Oncotype; ?role in T1b N0 and T1N1

Stage IIA-IIB

Stage IIB-III

Surgery, unless response could improve surgical options

NACT with AC-T

Neoadjuvant endocrine therapy with AI, unless grade 3 or high-risk Oncotype, then NACT with AC-T or TC

Surgery

If low risk (by clinical stage +/- Oncotype), adjuvant endocrine therapy with tamoxifen if premenopausal and AI > tamoxifen if postmenopausal If high-risk, (neo)adjuvant chemotherapy (AC-T or TC 4-6) followed by adjuvant endocrine therapy, including OFS in premenopausal

Premenopausal: Consider trial of tamoxifen; otherwise OFS and then follow postmenopausal algorithm

Postmenopausal: Letrozole + palbociclib, fulvestrant, or AI PD

Depending on 1st-line choice: fulvestrant (if AI +/- palbociclib) + palbociclib (if FDA approved and did not receive as 1st-line), any AI (if fulvestrant), exemestane (if a non-steroidal AI) +/- everolimus PD Depending on 1st- and 2nd- line treatments: fulvestrant +/-palbociclib, exemestane +/- everolimus, megestrol acetate or medroxyprogesterone, estradiol, or fluoxymesterone

Abbreviations: NACT = neoadjuvant chemotherapy; AI = aromatase inhibitor; AC-T = doxorubicin & cyclophosphamide followed or preceded by docetaxel or paclitaxel (weekly or dose-dense); TC= docetaxel & cyclophosphamide; OFS = ovarian function suppression; PD = progressive disease

Figure 1 Treatment algorithm for hormone receptor–positive, HER2-negative breast cancer (HRþ/HER2 BC). AC-T, doxorubicin and cyclophosphamide followed or preceded by docetaxel or paclitaxel (weekly or dose dense); NACT, neoadjuvant chemotherapy; PD, progressive disease; TC, docetaxel and cyclophosphamide. (Color version of figure is available online.)

was a relatively small study (n ¼ 1172).1 However, the National Cancer Institute of Canada (NCIC) MA.17 trial, which compared 5 years of the aromatase inhibitor (AI) letrozole with placebo in postmenopausal women who were free of disease after 5 years of tamoxifen, demonstrated a 48% improvement in disease-free survival (DFS) and a 39% improvement in overall survival (OS), taking into account crossover from placebo to letrozole when the initial results of the study were announced, illustrating the potential benefit of extended adjuvant endocrine therapy.2,3 Further analysis revealed that younger patients, those who were premenopausal when they started tamoxifen but postmenopausal 5 years later when they transitioned to the AI, received the largest benefit from this treatment.4 The dilemma was how to treat women who were either still premenopausal after 5 years of tamoxifen or unable to tolerate an AI owing to side effects, most often joint stiffness and pain, vaginal dryness and atrophy, and mood swings. The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and adjuvant Tamoxifen—To offer more (aTTOM) trials, which were initiated in 1996 and included more than 22,000 women, assessed the benefits and risks of extended adjuvant therapy with tamoxifen.5,6 Results reported in 2012-2013 demonstrated that although patients with HRþ cancers (n ¼ 9600)

assigned to continue tamoxifen had minimal reductions in recurrences and breast cancer–attributed deaths during their additional 5 years of treatment, their risks of recurrence and death from breast cancer were significantly (25%-30%) lower in years 10-15 and beyond, reflecting the indolent and insidious nature of these cancers. The only major side effect of extended treatment with tamoxifen was a doubling of the incidence of endometrial cancer, from 1.2%-2.4%. The benefit of extending adjuvant endocrine therapy beyond 5 years in patients treated with an AI—either alone or after 2-3 years of tamoxifen—are less clear; reports from 2 studies that address this matter—NSABP B-42 and MA.17 R —are eagerly awaited. Pending those findings, oncologists may recommend extending treatment with an AI to 5 years in patients who started it after 2-3 years of tamoxifen or, in higher risk patients who are tolerating it well, simply continuing the AI until these study results become available. Patients whose oncologist recommends stopping the AI (for now) may be comforted by the knowledge that, in both MA.17 and the recently reported LATER trial, patients who started an AI after a break of up to several years still benefited from this treatment.7,8 Despite its potential advantages, the decision to recommend extending adjuvant endocrine therapy should take into

Advances in medical management of breast cancer: 2015 account the patient's likelihood of benefiting as well as the side effects and other risks of that treatment. For example, a patient with a small, node-negative cancer would be expected to have no more than a 1%-2% additional reduction in risk of recurrence with continued treatment with either tamoxifen or an AI, whereas patients with larger or node-positive cancers have a much higher residual risk of recurrence after 5 years. Although there is no way of knowing which patients are going to develop a late recurrence, genomic tests such as the Breast Cancer Index, performed on the original surgical specimens, may help to classify patients as either low risk, in whom endocrine therapy could be discontinued, or high risk, who are more likely to benefit from continuation of treatment.9 The superiority of an AI over tamoxifen as adjuvant therapy in postmenopausal patients was confirmed by a recently published meta-analysis,10 with significant reductions in recurrences (26% at 5 years and 20% at 10 years, resulting in a 3.6% absolute improvement) and breast cancer mortality (15% at 10 years, resulting in a 2.1% absolute improvement). With an AI, endometrial cancer rates were lower (0.4% vs 1.2% at 10 years), fracture rates were higher (8.2% vs 5.5% at 5 years) and non–breast cancer mortality was similar. Patients who received 2-3 years of tamoxifen before switching to an AI had higher recurrence rates for the first few years than patients treated initially with an AI, though the difference in breast cancer mortality at 10 years was not significant, and results with this group were still superior to those who received only tamoxifen. The value of OFS, either surgical (bilateral oophorectomy) or medical (with a long-acting luteinizing hormone–releasing hormone analog such as goserelin or leuprolide), in premenopausal women with HRþ cancers has been investigated for many years, but prior studies were confounded by either the absence of an appropriate control arm or the uncertainty of ovarian recovery after chemotherapy, which varies by patient age and regimen administered. As tamoxifen competes with estrogen for binding to the estrogen receptor (ER), lowering the estrogen level might improve its efficacy; moreover, with OFS patients have the option of being treated with an AI in place of tamoxifen. In the Tamoxifen and Exemestane Trial (TEXT), premenopausal patients were stratified by whether or not they had received chemotherapy, but all underwent OFS and were randomized to tamoxifen or exemestane (an AI). In the Suppression of Ovarian Function Trial (SOFT), a control arm—tamoxifen without OFS—was added, and patients who had received chemotherapy were required to have evidence of recovery of ovarian function—either resumption of menses or a premenopausal estrogen level—within 8 months of completing that treatment. A combined analysis of the 2 common arms of the trials confirmed the superiority of the AI over tamoxifen in the setting of OFS.11 The more eagerly awaited results from SOFT revealed a dichotomy—although low-risk patients, who had not received chemotherapy, did very well with tamoxifen alone and did not achieve significantly better results with OFS with either tamoxifen or exemestane, highrisk patients, who had received chemotherapy, did much better with OFS and with exemestane over tamoxifen.12

61 Patients under the age of 35 had the largest benefit from OFS and exemestane. OFS was associated with increased hot flashes, vaginal dryness, and reduced libido, and would be expected to increase bone mineral loss, thus in recommending this treatment oncologists have to balance its effect on a patient's quality of life against her likelihood of benefit. Whether OFS should be extended beyond 5 years in very young women with HRþ cancers has not been studied. As risk categorization for patients enrolled on SOFT did not include a genomic assay such as Oncotype Dx (see later), its availability raises challenging questions, such as whether patients who would have received chemotherapy in the past but do not as a result of a low-risk genomic assay and patients with early stage cancers who might not have received chemotherapy in the past but get this treatment owing to a high-risk genomic assay would benefit from OFS and administration of an AI over tamoxifen alone. In the past, neoadjuvant endocrine therapy, initially with tamoxifen, more recently with an AI, was reserved for women with larger or unresectable cancers believed to be too old or frail for neoadjuvant chemotherapy. With the realization that many HRþ/HER2 cancers achieve little response to chemotherapy but may be very sensitive to estrogen deprivation, the population of patient in whom this approach is contemplated has expanded considerably. ACOSOG Z1031 randomized postmenopausal patients with HRþ/HER2 cancers to one of the 3 US Food and Drug Administration (FDA) approved AIs—anastrozole, letrozole or exemestane—for 14 weeks.13 Although no substantial differences were seen in clinical response rates between the 3 agents, and few patients achieved a pathologic complete response (pCR), many patients who would have required a mastectomy at study entry became candidates for breastconserving surgery (BCS). The Preoperative Endocrine Prognostic Index (PEPI) score, which takes into account tumor and nodal stage, endocrine sensitivity (ER expression), and proliferative rate (Ki67) after neoadjuvant treatment, has been developed to distinguish patients with a good prognosis who would likely not benefit from subsequent adjuvant chemotherapy (PEPI ¼ 0) from those who might (PEPI Z 1). Measurement of Ki67 on a biopsy taken after 2-4 weeks of neoadjuvant endocrine therapy has been proposed to identify patients more (low Ki67) or less (high Ki67) likely to achieve a PEPI ¼ 0. Recognizing the slower response to endocrine therapies than with neoadjuvant chemotherapy, the standard duration of neoadjuvant endocrine therapy (in responding patients) has been expanded from 3-4 months to 6 months. The recognition of significant biologic diversity within HRþ/HER2 tumors, which may determine both risk of recurrence and benefit from both endocrine therapy and chemotherapy, encouraged the development of genomic assays, including Oncotype Dx and Mammoprint. At some institutions, submission of tissue for one of these assays—most often Oncotype Dx—has become “reflex” for node-negative HRþ/HER2 cancers of a defined size (such as 41 cm) in certain patient populations (such as younger than the age of 60 or 70 years). That way, results are available for the patient's postoperative consultation with medical oncology to discuss the role of adjuvant chemotherapy in an early stage cancer if

62 the test suggests a biologically more aggressive cancer than previously suspected. Studies suggest that this test alters treatment recommendations in 20%-30% of patients, more often leading the oncologist to recommend omitting chemotherapy than suggesting chemotherapy when endocrine therapy alone would have been the recommendation. The use of these assays in node-positive patients is less well established, but may be useful in patients with limited nodal involvement. Results from trials like Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) (also known as Program for the Assessment of Clinical Cancer Tests [PACCT-1]), which randomized node-negative patients with an intermediate risk Oncotype Dx Recurrence Score to chemotherapy or not, are eagerly anticipated. A similar trial, Rx for Positive Node, Endocrine Responsive Breast Cancer (RxPONDER), also known as SouthWest Oncology Group (SWOG) 1007, is ongoing for patients with limited node-positive cancers (1-3 nodes with macrometastases) with low- or intermediate-risk Recurrence Scores. A controversial issue in the management of stage I-III HRþ/ HER2 breast cancers is the role of bisphosphonates in the adjuvant setting. Bone is the most common site of distant disease recurrence in patients with this subtype of breast cancer. Preclinical studies suggest that bisphosphonates may possess inherent antitumor activity, and that bisphosphonateinduced osteoclast inhibition may make the bone microenvironment less supportive of the establishment of bone metastases. Reports from studies performed primarily to assess the effect of bisphosphonates on treatment-related osteoporosis and bone fractures in patients with induced menopause suggested a recurrence-free survival benefit, leading to a number of studies that examined this question directly. Although results from the individual studies were mixed, a recently published meta-analysis that included more than 18,000 women from 26 clinical trials demonstrated an 18% reduction in distant recurrences at 10 years in postmenopausal patients, owing solely to a 28% reduction in the incidence of bone metastases, which translated into a 3.3% absolute reduction in breast cancer mortality, with no improvement seen in younger women, distant recurrences outside of bone or contralateral breast cancers.14 This has led some to hypothesize an interaction between osteoclast activation in the setting of a low estrogen level and a more hospitable environment for circulating breast cancer cells that is altered by these agents. In a recently reported study (that did not include a no-treatment arm) of more than 6000 women with stage I-III cancers treated for 3 years there was no difference in DFS and minimal differences in toxicities between the intravenous bisphosphonate zoledronic acid and the oral agents clodronate and ibandronate.15 Although most patients expressed a preference for an oral agent if equally effective, as neither clodronate nor ibandronate (at the dose used in this study) is approved in the United States, the currently available treatment option is zoledronic acid 4 mg administered intravenous every 6 months for 3 years. Its usage varies widely, with some oncologists opting to wait for further data and reserving its use for patients with documented osteoporosis or a

S. Witherby et al. significant decline in bone mineral density following initiation of adjuvant endocrine therapy, others selectively administering it to high-risk patients, and others recommending it more broadly to their postmenopausal patients (and also to higherrisk premenopausal patients undergoing OFS).

HRþ/HER2 Metastatic Breast Cancer Except in patients who present with extensive visceral (usually liver or lung) or very symptomatic metastatic disease, who often receive chemotherapy first, HRþ/HER2 metastatic breast cancer (MBC) is typically treated with a sequence of endocrine therapies unless or until they exhibit resistance to such treatments, at which point they are switched to chemotherapy (Fig. 1B). Recent clinical trial results have led medical oncologists to rethink the sequence of endocrine therapies, especially in postmenopausal women, and to consider the addition of targeted therapies to delay the development of resistance. In 2015, first-line endocrine therapy options for postmenopausal patients include an AI, fulvestrant (an ER antagonist), the combination of fulvestrant and an AI, and the combination of an AI with the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib. First-line endocrine therapy for premenopausal patients consists of tamoxifen alone or, following OFS, tamoxifen or any of the options available to postmenopausal patients. Fulvestrant binds to the ER with much greater avidity than tamoxifen, and not only blocks activation of estrogenresponsive genes but promotes degradation of the ER, which is why it is sometimes referred to as a selective ER downregulator (SERD). As a second- or third-line endocrine agent, its use is associated with a median time to progression of only 3-4 months, comparable to that seen with switching to the steroidal AI exemestane after progression on a nonsteroidal AI.16,17 A more intensive regimen (500 mg intramuscularly (IM) on days 1 and 15 then every 28 days) has been shown to be more effective than the initially approved dose and schedule (250 mg IM every 28 days).18 In the phase II FIRST trial, first-line fulvestrant improved median time to progression (mTTP) by 10 months (23 vs 13 months) over anastrozole despite similar overall response rates (ORR) and was associated with fewer side effects.19 In updated results presented at the 2014 San Antonio Breast Cancer Symposium (SABCS), patients assigned to fulvestrant also had an increase in median OS (mOS) from 48-54 months.20 A much larger phase III trial comparing fulvestrant with anastrozole in the first-line setting (FALCON) has completed accrual. The phase III SWOG 0226 trial compared singleagent anastrozole with the combination of anastrozole and fulvestrant as first- or second-line endocrine therapy, using a fulvestrant dose of 250 mg IM for days 1 and 15, then every 28 days.21 Although treatment with the combination yielded only a modest improvement in median progression-free survival (mPFS), there was a more significant increase in mOS (48 vs 41 months), though this benefit appeared to be limited to first-line patients. Pending future results, some oncologists are recommending first-line treatment with fulvestrant, whereas others suggest combination therapy with fulvestrant and an AI,

Advances in medical management of breast cancer: 2015 reserving treatment with an AI alone for patients who decline the IM injections. Although a significant fraction of HRþ/HER2 patients with MBC initially respond to first-line endocrine therapy, some progress rapidly and a significant fraction progress within 6-12 months of starting this treatment. One of the hallmarks of endocrine resistance is increased cellular proliferation and overexpression of cyclin D1, which in turn activates CDK 4/6, which enable progression through the cell cycle and cell division. Palbociclib is a highly selective oral CDK 4/6 inhibitor that demonstrated preferential inhibition of HRþ/HER2 breast cancer cell lines in vitro.22 The phase II PALOMA-1 trial compared letrozole with the combination of letrozole and palbociclib as first-line therapy for postmenopausal women with HRþ/HER2 MBC. Adding palbociclib significantly improved mPFS (from 10-20 months) and ORR (from 39%-55%).23 Although there was no significant improvement in mOS (37.5 vs 33 months, P ¼ 0.81), the FDA granted palbociclib accelerated approval in February 2015, pending confirmation from the PALOMA-2 phase III study. The recently reported phase III PALOMA-3 trial demonstrated that adding palbociclib to fulvestrant in patients with HRþ/HER2 MBC who had progressed on prior endocrine therapy increased mPFS from 3.8-9.2 months compared with fulvestrant alone.24 Given these results, it seems likely that the FDA will approve the use of palbociclib with fulvestrant in the near future, though whether that will include patients receiving fulvestrant as first-line endocrine therapy is unclear. Owing to its antiproliferative effects, treatment with palbociclib is associated with a 450% incidence of grade 3-4 neutropenia, though this is typically asymptomatic, and with modest increases in fatigue, nausea, anemia, diarrhea, and low-grade infections. To what extent these toxicities and the cost of this agent ($10,000-$11,000 per month) may limit its use are not yet known. Endocrine resistance has also been attributed to aberrant activation of intracellular signaling pathways that bypass the block caused by estrogen deprivation. One of the most commonly mutated genes in HRþ/HER2 cancers is PIK3CA, which can lead to constitutive activation of the PI3K/Akt/mTOR signaling pathway. In the phase III BOLERO-2 trial, patients with HRþ/HER2 MBC who had progressed on a nonsteroidal AI assigned to treatment with the oral mTOR inhibitor everolimus in combination with exemestane had superior mPFS (7 vs 3 months) compared with exemestane alone.25 Although this resulted in FDA approval of this combination in the second-line setting, uptake by oncologists and their patients has been limited by toxicities (stomatitis, anemia, fatigue, dyspnea, hyperglycemia, and noninfectious pneumonitis), drug costs, and the lack of a significant survival benefit. In premenopausal women with HRþ/HER2 MBC, although some oncologists will try single-agent tamoxifen in patients with asymptomatic or minimally symptomatic disease, in a meta-analysis of 4 randomized trials the addition of OFS suppression was shown to improve mPFS and mOS.26 Although randomized trial data on the benefits of substituting either an AI or fulvestrant for tamoxifen following OFS in this setting are lacking, given their superiority in postmenopausal

63 women many oncologists have adopted this approach. Finally, as the standard of care is to not permit a patient's ovarian function, once suppressed, to recover, and as recovery of ovarian function on luteinizing hormone–releasing hormone analogs has been known to occur, patients who are initially treated with one of these agents are often encouraged to undergo bilateral oophorectomies. An unanswered question in the management of HRþ/ HER2 MBC is whether patients without symptomatic or extensive visceral disease would benefit from upfront chemotherapy, rather than deferring this treatment until they progress on one or more endocrine therapies. There are no good trials addressing this question, and perhaps the advent of effective targeted therapies will make it moot. Similarly, although endocrine therapy is often administered after first- or subsequent-line chemotherapy in responding patients when response plateaus or excessive toxicity develops, the benefits of this approach in improving mPFS or mOS have not been tested in a randomized trial. Progestational agents like megestrol acetate, pharmacologic doses of estrogen (such as estradiol 2 mg 3 times a day), and androgens like fluoxymesterone have all demonstrated some activity in HRþ/HER2 MBC after progression on the agents discussed above. As with all subtypes of MBC, early incorporation of palliative care in the setting of incurable disease is appropriate.

HER2-Positive Breast Cancer Identification of HER2 and the gene that encodes for it on chromosome 17, recognition that amplification, and consequent overexpression, of that gene in approximately 20% of human breast cancers results in a biologically aggressive and relatively endocrine therapy- and chemotherapy-resistant malignancy, and demonstration that administration of agents, initially the monoclonal antibody trastuzumab, which interfere with the ability of that receptor to activate signaling pathways that promote tumor cell survival, proliferation, and metastasis results in sizable improvements in mPFS and mOS in women with HER2þ breast cancer have been among the most important advances in medical oncology in the past 15 years (Fig. 2). Studies completed, presented and published over the past few years have addressed efforts to enhance the efficacy or reduce the toxicity of standard chemotherapy plus trastuzumab regimens, in both early stage and advanced disease, and to deal with patients whose cancers have become refractory to those treatments. HER2 is a transmembrane receptor. Trastuzumab binds to the extracellular portion of the receptor adjacent to the cell membrane, blocking the conformational change triggered by formation of HER2 homodimers, which is necessary to activate the tyrosine kinase moiety on the intracellular portion of the receptor, thus, preventing initiation of the signal transduction cascade responsible for its biologic activities. One proposed mechanism for resistance to trastuzumab is loss of this extracellular domain; by directly inhibiting the receptor's tyrosine

S. Witherby et al.

64

B Stage IV

A Stage I-III

Stage I

Stage IIA-IIB

Surgery

Surgery, unless response could improve surgical options

If path stage unchanged adjuvant wP + H for T1b/cN0; ? benefit in T1aN0

Stage IIB-III

NACT with TCHP or AC-TH

T + HP or wP + HP (in poor PS patients could consider endocrine therapy + H if HR+ or T-DM1 if covered) PD T-DM1 PD

NACT with TCH (+P if T>3cm or N+) or ACTH+/- P Adjuvant TCH, TCyH or AC-TH, then

Surgery

Non-cross-resistant chemo (liposomal doxorubicin, vinorelbine, gemcitabine, capecitabine, eribulin, ixabepilone, etc.) + H, capecitabine + lapatinib, lapatinib + H (may favor lapatinib-containing regimen if patient has brain mets)

Adjuvant T to complete a year and adjuvant endocrine therapy if HR+ Abbreviations: wP = weekly paclitaxel; H= trastuzumab; NACT = neoadjuvant chemotherapy; TCH = docetaxel, carboplatin & trastuzumab; P=pertuzumab; AC-TH = AC followed or preceded by docetaxel or paclitaxel + H; TCyH = docetaxel, cyclophosphamide & H; HR+ = hormone receptorpositive; T-DM1= trastuzumab emtansine; PD = progressive disease

Figure 2 Treatment algorithm for HER2-positive breast cancer (HER2þ BC). AC-TH, AC followed or preceded by docetaxel or paclitaxel þ H; H, trastuzumab; HRþ, hormone receptor positive; NACT, neoadjuvant chemotherapy; P, pertuzumab; PD, progressive disease; TCH, docetaxel, carboplatin, and trastuzumab; TCyH, docetaxel, cyclophosphamide, and H; T-DM1, trastuzumab emtansine; wP, weekly paclitaxel. (Color version of figure is available online.)

kinase, lapatinib, which, in combination with the oral chemotherapy agent capecitabine, may be effective in HER2þ cancers that progressed on trastuzumab, retains activity against these mutated cells. However, lapatinib also inhibits the tyrosine kinase of the epidermal growth factor receptor (also known as HER1), leading to doselimiting diarrhea and rash similar to that seen with other epidermal growth factor receptor–targeted agents. Another proposed mechanism for trastuzumab resistance is the formation of HER2:HER3 heterodimers, the biologic activity of which is not blocked by trastuzumab. Pertuzumab binds to HER2 at a different site than trastuzumab, and blocks the formation of these dimers. In patients who had progressed on a trastuzumab-containing regimen, the combination of pertuzumab with trastuzumab yielded an ORR of 25%, and half of these patients either responded or had stable disease lasting at least 6 months.27 The CLEOPATRA trial assessed the addition of pertuzumab to the combination of docetaxel and trastuzumab as first-line therapy for HER2þ MBC, and demonstrated statistically significant improvements in PFS (18.5 vs 12.4 months), ORR from (80% vs 69%), and, as reported earlier this year, mOS (56.5 vs 40.8 months).28,29 This led to FDA approval of pertuzumab for HER2þ MBC,

and general acceptance of the docetaxel, trastuzumab, and pertuzumab (THP) regimen as standard first-line therapy, though it should be noted that patients assigned to the control arm of the study did not cross over to pertuzumab as salvage therapy. The addition of pertuzumab was associated with higher rates of diarrhea, mucositis, and rash, raising interesting questions as to role of HER2 heterodimers in normal tissues, and febrile neutropenia, but no increase in the incidence of cardiac toxicity. A recently published phase II study demonstrated similar results with weekly paclitaxel, trastuzumab, and pertuzumab with fewer acute chemotherapy-related toxicities,30 and other chemotherapeutic agents such as vinorelbine have also been given with the antibody combination. If a patient develops persistent chemotherapy-related toxicities, or her response to treatment plateaus, the chemotherapeutic agent can be discontinued and the dual antibody therapy continued until disease progression, as was allowed on CLEOPATRA, sometimes with the addition of an endocrine agent in the 50%-60% of patients who are also HRþ. Although studies support continuation of trastuzumab with second- and subsequent-line therapy in HER2þ patients who progress, no such data exists for pertuzumab and thus this cannot be recommended.

Advances in medical management of breast cancer: 2015 Another promising agent for patients with HER2þ MBC is the antibody-drug conjugate (ADC) trastuzumab emtansine, also known as T-DM1, which consists of a potent antimicrotubule agent (emtansine) linked to trastuzumab which is activated only after the trastuzumab moiety, bound to HER2, is endocytosed and the linker digested, designed to minimize exposure of normal tissues. After demonstrating an ORR of 26% in patients who had progressed while on or shortly after discontinuing a trastuzumab-containing regimen,31 T-DM1 was compared in 2 phase III studies with either the combination of capecitabine and lapatinib (EMILIA) and to treatment of physician's choice (TPC) (TH3RESA) in patients previously treated with a trastuzumab-containing regimen.32,33 In EMILIA, T-DM1 was not only significantly more effective (mPFS ¼ 9.6 vs 6.4 months and mOS ¼ 30.9 vs 25.1 months) but also better tolerated, with thrombocytopenia and elevated transaminases the only toxicities seen more commonly with the ADC. Similar results were reported from the Th3RESA trial, with mPFS of 6.2 months for T-DM1 vs 3.3 for TPC and a mOS trend favoring the ADC. On the basis of the EMILIA results, trastuzumab emtansine was approved as second-line therapy for HER2þ MBC, and is currently considered the standard of care in this setting. Treatment with this agent is usually continued until disease progression or toxicity (neuropathy, thrombocytopenia), with a significant proportion of patients continuing treatment for 12 months and longer with minimal toxicity. The MARIANNE study was designed to determine if singleagent T-DM1 or the combination of T-DM1 and pertuzumab could replace a taxane-trastuzumab regimen as standard firstline therapy for HER2þ MBC. As reported at this year's American Society of Clinical Oncology (ASCO) meeting, whereas both T-DM1-containing regimens were equivalent in efficacy to docetaxel or paclitaxel (physician's choice) and trastuzumab (mPFS ¼ 13.7 vs 14.1 and 15.2 months for single-agent T-DM1 and T-DM1 plus pertuzumab, respectively), neither was superior.34 Responses on the T-DM1 arms were more durable, likely owing to chemotherapy-related toxicities limiting the duration of treatment on the control arm, and side effects, ranging from febrile neutropenia to alopecia, were much less common. The investigators could not explain the lack of added benefit with the addition of pertuzumab to TDM1. Given the results from the CLEOPATRA trial, THP remains the standard first-line regimen in HER2þ MBC, but in patients hoping to avoid hair loss and other toxicities, singleagent T-DM1 may be an appealing alternative, assuming coverage for both first-line T-DM1 and salvage therapy with a pertuzumab-containing regimen, neither of which are consistent with their current FDA indications. In patients who progress on first-line THP and second-line T-DM1, third-line options range from combinations of nontaxane chemotherapeutic agents (vinorelbine, liposomal doxorubicin, gemcitabine, capecitabine, eribulin, ixabepilone, etc.) with trastuzumab, the combination of capecitabine and lapatinib, which may be especially appealing in patients with brain metastases, as lapatinib can penetrate the CNS, whereas trastuzumab does not, trastuzumab and lapatinib together, or a clinical trial of any of a number of novel HER2-targeted agents.

65 Combinations of endocrine therapy and HER2-targeted agents (such as anastrozole or tamoxifen with trastuzumab or letrozole with lapatinib) have demonstrated superior efficacy to endocrine therapy alone in patients with HRþ/ HER2þ cancers, but appear to be less effective than chemotherapy-based combinations, though a randomized study to test this has not been performed, and thus are generally reserved for older or frail patients, except when given to patients who responded to a chemotherapy-based combination as mentioned above. The addition of trastuzumab to adjuvant chemotherapy for HER2þ early stage breast cancer improves DFS by 40%-50% over chemotherapy alone. The first wave of HER adjuvant trails used anthracycline-containing regimens—AC followed by a taxane, with trastuzumab given concurrent with or sequentially after the taxane (AC-TH). BCIRG 006 demonstrated that either AC-TH or a non–anthracycline-containing regimen, docetaxel, carboplatin, and trastuzumab (TCH) was superior to AC-T alone.35 Although DFS and OS curves for the AC-TH arm tracked above those for the TCH arm, the study was not powered to compare these 2 regimens, and any modest advantages favoring AC-TH may be offset by a higher incidence of congestive heart failure rate (2% vs 0.4%) and a doubling of patients with asymptomatic declines in cardiac function (18.6% vs 9.4%). No other study has directly compared AC-TH with TCH in the adjuvant setting, but on studies where treating physicians were allowed to choose between the two, U.S. and European medical oncologists have “voted with their feet” in favor of TCH by a margin of 9:1. The BETH trial failed to demonstrate a benefit from the addition of the antiangiogenic antibody bevacizumab to adjuvant chemotherapy and trastuzumab, but confirmed excellent outcomes associated with the TCH regimen, with invasive DFS ¼ 92% (88% in node positive, 96% in node negative) at 38 months.36 Results from the APHINITY trial, which tests the addition of pertuzumab to either TCH or AC-TH in a largely node-positive population, are eagerly awaited to see if this already low recurrence rate can be reduced further. Although effective, both TCH and AC-TH may be too toxic to justify their use in lower risk HER2þ patients, especially those with T1a/bN0 cancers, even though their risk of recurrence without adjuvant treatment may be as high as 15%-20%. After concluding that a randomized study with a no-treatment control arm could not accrue, a single arm study was conducted in node-negative patients with tumors up to 3 cm given weekly paclitaxel and trastuzumab for 12 weeks followed by trastuzumab every 3 weeks to complete a year of treatment. At 3 years, DFS is 98.7%, leading this less toxic regimen to be widely adopted to treat these lower risk patients.37 Given the challenges of conducting studies in the adjuvant setting—large patient numbers and relatively long follow-up required, especially as results with standard therapy improve —researchers have turned to the neoadjuvant setting and the use of pCR as a surrogate end point for longer-term outcomes to assess the benefit of novel therapies and combinations. The validity of this end point is supported by results from the NOAH trial and the FDA-sponsored meta-analysis, both of

66 which demonstrated a correlation between pCR and superior event-free survival (EFS) in HER2þ patients.38,39 The NeoALTTO trial compared the combination of trastuzumab and lapatinib with either single agents administered for 6 weeks by themselves then for 12 weeks in combination with weekly paclitaxel. Dual HER2-targeted therapy was associated with a significant increase in the pCR rate (51.3% vs 29.5% for trastuzumab and 24.7% for lapatinib), and patients who achieved a pCR fared much better than those who did not (3-year EFS of 86% vs 72%, OS ¼ 94% vs 87%).40 However, there was no significant difference in long-term outcomes between patients who received dual HER-targeted therapy compared with singleagent trastuzumab (EFS ¼ 84% vs 76%), and when the much larger ALTTO adjuvant trial also failed to show a significant benefit for the addition of lapatinib to chemotherapy and trastuzumab,41 and that it was associated with increases in diarrhea, rash, and early treatment discontinuation, the question as to the role of lapatinib in early stage HER2þ cancers appears to have been settled. Fortunately, at around the same time, data on the benefit of adding pertuzumab to neoadjuvant chemotherapy and trastuzumab began to emerge. The randomized phase II NeoSphere trial demonstrated that the addition of pertuzumab to 4 cycles of docetaxel and trastuzumab increased the pCR rate from 29% (TH) to 46% (THP), whereas substitution of pertuzumab for trastuzumab reduced the pCR rate to 24%, and treatment with the 2 HER2-targeted antibodies alone yielded a pCR rate of 17%, demonstrating the power of HER2-blockade, especially in HR/HER2þ patients, in whom there was a pCR rate of 29%.42 All patients eventually received anthracycline-based adjuvant chemotherapy and completed a year of trastuzumab. The study was not powered to demonstrate a benefit in longterm outcomes, but patients who received THP had 5-year PFS of 86% compared with 81% for TH.43 In another randomized phase II study, TRYPHAENA, 3 different pertuzumabcontaining neoadjuvant regimens—FEC with or without concurrent trastuzumab and pertuzumab followed by THP or TCH with pertuzumab (TCHP)—demonstrated pCR rates exceeding 50%.44 On the basis of these 2 phase II studies, the FDA granted accelerated approval for the use of pertuzumab in the neoadjuvant setting in any of the regimens used in those trials. This approach has been widely adopted by the medical oncology community in patients with HER2þ cancers clinical stage IIA and higher, with TCHP chosen as the control neoadjuvant regimen for a number of randomized trials, and has increased the percentage of HER2þ patients being treated in the neoadjuvant setting, given that pertuzumab is not approved in the adjuvant setting, pending results from the APHINITY trial described above. A recently reported, moderated-sized (n¼130) randomized phase II neoadjuvant study in HRþ/HER2þ patients demonstrated a pCR rate of 40.5% with 4 cycles of T-DM1 alone and 45.8% with the combination of T-DM1 and endocrine therapy, rates that are higher for this patient subset than in NeoSphere, compared with only 6.7% with trastuzumab and endocrine therapy.45 Additional studies with this agent in the neoadjuvant setting are ongoing.

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Triple-Negative Breast Cancer Triple-negative breast cancer (TNBC) accounts for 15%-20% of breast cancers in the United States, but is more common in younger women, African-Americans and Hispanics, and in carriers of deleterious mutations in the BRCA1 gene (Fig. 3). Although some degree of variability within this entity, defined by what it does not have, has long been appreciated—pure medullary and the rare adenoid cystic carcinomas of the breast do not express hormone receptors or HER2, but behave very differently from “classic” TNBC—over the past few years the extent of this heterogeneity has become more apparent. By one type of gene expression analysis, 70%-80% of TNBC express a “basal-like” pattern, whereas the other 20%-30% are a mix of luminal, HER2-enriched (despite the absence of expression of hormone receptors or HER2), “normal-like” and “claudin-low” subtypes.46 In another analysis, 6 different subtypes were identified—2 basal-like and others labeled immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen—all of which may have different biologic behaviors and different susceptibilities to treatment,47 but have not been validated for routine use in clinical practice. Patients with metastatic TNBC continue to have a poor prognosis, with mOS of less than a year. Although patients often initially respond to chemotherapy, duration of response is typically brief, and briefer still with subsequent lines of therapy. Combination chemotherapy may yield a higher ORR, and thus is useful in symptomatic patients, but does not change the overall prognosis. Based on promising results from a randomized phase II study48 there was hope that the addition of a PARP inhibitor, iniparib (BSI-201), to the combination of carboplatin and gemcitabine, chosen to maximize DNA damage, would significantly prolong survival in metastatic TNBC, but the larger phase III study was negative,49 and it was subsequently discovered that iniparib was actually not an effective inhibitor of PARP, and there is little reason to favor the carboplatin-gemcitabine combination over other options except perhaps in patients who relapse within months of completing anthracycline- and taxane-containing adjuvant chemotherapy, a group with a particularly poor prognosis given demonstrated chemotherapy-resistant disease. Given the similarities in gene expression patterns between BRCA1-mutated cancers and sporadic TNBC, and the activity reported for single-agent cisplatin in the neoadjuvant setting for BRCA1-associated breast cancers,50 there has been a great deal of interest in determining whether platinum analogs should replace other agents as first-line therapy for metastatic TNBC. A study reported at the 2014 SABCS compared single-agent carboplatin with docetaxel in metastatic TNBC and BRCAassociated cancers. Response rates, median PFS and mOS were similar, except in the small (n ¼ 43) cohort of BRCA-associated cancers, in which carboplatin had a decided advantage (ORR ¼ 68% vs 33%, mPFS ¼ 6.8 vs 4.8 months).51 In patients with stage I-III TNBC, except perhaps those with very small (T1a/b) node-negative cancers, in whom risk of recurrence and thus the role of adjuvant chemotherapy remain controversial, results of a series of clinical trials performed over the last 15-20 years have determined optimal adjuvant therapy

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A Stage I-III

Stage I T1a/bN0

Surgery

If path stage unchanged OBS vs. adjuvant chemo TC or AC x4

B Stage IV

Stage I-IIA (T<3 cm)

Surgery, unless response could improve surgical options

Stage IIA (>3cm), IIB-III

NACT with ddAC + wP or ddP

Chemotherapy Single agent (anthracycline, taxane or other, depending on prior treatment; consider carboplatin if BRCA carrier) unless extensive or symptomatic disease (‘visceral crisis’) in which case combination (such as AC, A+Taxane, carboplatin/paclitaxel, carboplatin/gemcitabine, etc.) should be considered

NACT with ddAC + wP or ddP Adjuvant chemo with ddAC + wP or ddP

PD

Surgery

Salvage chemotherapy with noncross resistant agent, could add eribulin, ixabepilone, vinorelbine, capecitabine, gemcitabine, etc., to list

Abbreviations: OBS = observation; TC = docetaxel & cyclophosphamide; AC = doxorubicin & cyclophosphamide; NACT = neoadjuvant chemotherapy; ddAC = dose-dense AC; wP = weekly paclitaxel; ddP = dose-dense paclitaxel; PD = progressive disease

Figure 3 Treatment algorithm for triple-negative breast cancer (TNBC). AC, doxorubicin and cyclophosphamide; ddAC, dose-dense AC; ddP, dose-dense paclitaxel; NACT, neoadjuvant chemotherapy; OBS, observation; PD, progressive disease; TC, docetaxel and cyclophosphamide; wP, weekly paclitaxel. (Color version of figure is available online.)

to be a sequence of anthracycline-based chemotherapy such as dose-dense AC (ddAC) and paclitaxel administered either weekly or every 2 weeks. In recently updated results (median follow-up 12.1 years) from the Eastern Cooperative Oncology Group 1199 study, patients assigned to weekly paclitaxel had 31% improvements in both DFS and OS compared with every 3 week paclitaxel,52 whereas in SWOG 0221, which compared weekly vs every 2 weeks adjuvant chemotherapy, DFS and OS trends favored every 2 weeks paclitaxel  6 over weekly paclitaxel  12 in patients who received ddAC.53 Thus far, no additions to this regimen, including chemotherapeutic agents like gemcitabine or capecitabine or biologic agents such as bevacizumab, have been shown to improve outcomes. As in other breast cancer subtypes, investigators have turned to the neoadjuvant setting in the hope of more rapidly and efficiently identifying promising agents and regimens. The sequential regimens used in the adjuvant setting—weekly paclitaxel and ddAC—typically yield pCR rates of 30%-40% when administered to patients with stage II-III TNBC as neoadjuvant therapy, and there are compelling data from the FDA-sponsored metaanalysis as to the superior outcomes associated with achievement of a pCR in this subtype.38 In a number of neoadjuvant studies the addition of bevacizumab to a standard chemotherapy regimen increased the pCR rate,54-56 but thus far this has failed to demonstrate improvements in long-term outcomes.57,58 Coupled with its failure to improve DFS or OS in adjuvant trials,59,60 and the incidence of serious and sometimes life-threatening

toxicities associated with bevacizumab, this has dampened interest in further study of its role in early stage TNBC. In contrast, there is ongoing interest in the potential value of adding carboplatin. Significant increases in the pCR rates with the addition of carboplatin, with higher rates of hematologic toxicities, and dose modifications were demonstrated in 2 fairly large studies (315 and 443 patients, respectively).55,61 One of these studies also demonstrated higher rates of conversion from mastectomy-requiring to BCS-eligible and from node positive to pathologically node negative in patients assigned to carboplatin.55 However, until there is evidence that these higher pCR rates translate into improvements in long-term outcomes, adding carboplatin is unlikely to be accepted as the standard of care, though some oncologists in the United States and elsewhere are incorporating it in the neoadjuvant regimen, especially for patients with larger or locally advanced TNBC. Whether a PARP inhibitor will enhance the efficacy of the platinum analog in this setting is also being studied.62

Controversies and Promising Directions Immunotherapy As our understanding of the immune system and how cancers avoid its surveillance and control increases, we are just

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68 beginning to harness its capacities to assist in our battle against malignancies. The uses of immune checkpoint inhibitors to circumvent ways in which cancers block immune recognition and attack have resulted in newly approved agents in metastatic melanoma and non–small cell lung cancer, and are being studied in a wide range of cancers including breast cancer. Studies presented at the 2014 SABCS and the 2015 AACR meetings demonstrated antitumor activity in patients with heavily pretreated metastatic TNBC for both the PD-1 inhibitor pembrolizumab and the PD-L1 inhibitor MPDL3280A.63,64 These and similar agents are being tested, alone and in combination with chemotherapy, in less heavily pretreated TNBC patients, including as adjuvant therapy in high-risk patients, such as those with significant residual disease after neoadjuvant chemotherapy, and will certainly be tested in other breast cancer subtypes as well. Within a few years, we should know if this approach can have a substantial effect on breast cancer recurrence, progression, and mortality.

Role of Bevacizumab and Other Antiangiogenic Agents As mentioned above, although the importance of neoangiogenesis in supporting the survival and spread of breast cancer is well supported, and there have been tantalizing hints of antitumor activity for bevacizumab when given in combination with chemotherapy in both the metastatic and neoadjuvant settings, this has not translated into clinically relevant improvements in long-term outcomes (recurrence-free survival or OS). But the questions remains—is there an identifiable subset of tumors in which antiangiogenic therapy could demonstrate more substantial and durable efficacy; and—is bevacizumab simply not the best choice for breadth and depth of antiangiogenic activity. Novel agents able to block multiple angiogenic pathways and thus prevent resistance to the relatively selective action of bevacizumab are being tested.

Genomic Assays—Ready for Prime Time? HER2-Targeted Therapy in HER2 “Negative” Patients As we do not have an accurate marker of HER2-dependence, it is likely that some of the patients currently received HER2targeted therapies do not benefit from these treatments and that some patients labeled HER2-negative would benefit from their inclusion. One hint of this came from the NSABP B-31 adjuvant trial, which included a small number of patients whose HER2-positive status, defined by a local lab, was not be confirmed on central testing. Despite being “HER2-negative” these patients derived as much benefit from the addition of trastuzumab to their adjuvant chemotherapy as patients who were HER2þ by standard criteria.65 To determine whether this was a chance observation or a biologically relevant phenomenon, NSABP conducted the B-47 trial, on which patients with HER2-1þ and HER2-2þ cancers without HER2 gene amplification by fluorescence in situ hybridization (FISH) were randomized to standard chemotherapy with or without trastuzumab. This study has completed accrual, and although we will likely not see results for several years, it could revolutionize our thinking about HER2-positivity and which patients may benefit from anti-HER2 therapy.

Endocrine Therapy in HRþ/HER2þ Patients In the neoadjuvant setting, pCR rates with neoadjuvant chemotherapy and HER2-targeted therapy are typically significantly lower in patients whose tumors are HRþ compared with those which are HR. Is this caused by biologic differences between the 2 subtypes—FISH ratios are typically higher in HR/HER2þ tumors, and higher FISH ratios are predictive of a greater likelihood of achieving pCR—or is “cross-talk” between the ER and the pathways activated by HER2 responsible for relative resistance to therapy? NSABP B-52 was designed to assess whether the addition of estrogen deprivation will significantly raise the pCR rate achieved with the TCHP neoadjuvant regimen.

The increased speed and decreased cost of performing whole exome sequencing has resulted in an explosion of interest in testing patients’ tumors to identify hitherto unsuspected driver mutations, which could potentially be targeted by agents already approved in other settings or by investigational agents. Although this technology is intriguing, and the testing often identifies a number of abnormalities in the cancer cells, the percentage of patients in whom a targetable mutation is detected is low, and the overall benefit of this still costly testing is unclear. Instead of paying for a commercial test off study, patients should be encouraged to have this type of testing done in the setting of a clinical trial that would not only cover the cost of the test but also help them gain access to investigational agents should the test identify a potential target. Such studies are being initiated by both the National Cancer Institute and American Society of Clinical Oncology.

Conclusions The last few years have witnessed major advances in our understanding of the biology of breast cancer that have led to promising new treatments for all the major subtypes of the disease, and to some success in tailoring or “personalizing” therapy to try to reduce toxicity without sacrificing efficacy. It is reasonable to expect that patient outcomes will continue to improve. However, we need to use the increasing sophistication of the tools at our disposal to analyze tumors, and to comb through the volume of data produced by those analyses, to identify biomarkers predictive of benefit, or lack thereof, from our novel therapies, given the toxicities, and sometimes staggering costs associated with them, especially when we seek to test agents associated with (often modest) improvements in outcomes in the metastatic setting in early stage disease.

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