Blog - Στυλιανός Γιασσάς Ιατρός Ογκολόγος

Patients with metastatic breast cancer are unlikely to be cured of their disease by any means. Complete remissions from systemic chemotherapy are uncommon, and only a fraction of complete responders remain progression free for a prolonged period. The median survival for patients with stage IV breast cancer is 18 to 24 months, although the range extends from only a few months to many years [1-3].

Although systemic therapy is the mainstay of treatment for metastatic breast cancer, local management of the primary as well as metastasis-specific local treatment (ie, metastasectomy, radiofrequency ablation, cryotherapy, and radiation therapy) may palliate symptoms and prevent cancer-related complications. Some evidence suggests a potential for prolonging survival, although data are limited [4].

The primary role of local treatment to the breast in metastatic breast cancer is palliation. Patients with metastatic disease should be evaluated for possible local management of the primary if it may control local complications from the cancer (eg, bleeding, infection, or wound management). However, in general, for patients who are asymptomatic at the site of their primary, we do not offer local treatment given lack of clear evidence that it improves survival. While retrospective evidence suggests a possible benefit, prospective data have shown no overall survival (OS) benefit or only minimal survival benefit, and are limited by methodologic issues. As such, we typically do not offer surgery in such cases.

Deviations to this approach may be rarely made on a case-by-case basis in a multidisciplinary setting, although these instances are exceptional. For example, we have offered local management of the primary to patients with human epidermal growth factor receptor 2 (HER2)-positive disease who have a brisk and dramatic response to systemic therapy, or when systemic disease is well controlled with systemic therapy but the primary site is progressing. However, the decision to proceed with local management in a similar situation should take into account patient preferences and should be made in a multidisciplinary setting.

Patients who present with symptomatic metastases, eg, intractable pain, loss of function, or an oncologic emergency (eg, cord compression, mass effect due to brain metastases, pathologic fracture due to a bony metastasis), are appropriate candidates for urgent local intervention to relieve symptoms and preserve patient ability to function. The objective of this treatment is palliative to relieve symptoms and to stabilize the patient rather than to prolong survival outcomes.

Additionally, for patients with a first presentation of metastatic disease, biopsy of the metastatic site should be performed to confirm the diagnosis and reestablish receptor status.

For patients who lack symptomatic metastases, systemic therapy without surgical intervention is usually the most appropriate treatment. While retrospective data suggest a survival benefit for aggressive local therapy in patients with oligometastatic disease [4-7], selection bias may have played a role in these studies. Prospective data are not available.

In the absence of conclusive data, some experts use systemic treatment alone for asymptomatic patients; others adopt an individualized approach to the asymptomatic patient, offering local management to those with multiple good prognostic factors, although this is not considered standard of care at this time:

●Good performance status –The most important issues in choosing patients for local treatment of metastatic disease are the performance status and an estimation of the relative risks of a planned operation. Asymptomatic patients without imminent risk of significant organ dysfunction with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or worse should not proceed with local management, as they are likely to have high rates of postoperative morbidity and mortality.

● Multivariable analysis of local treatment outcomes suggests that those patients with limited metastatic disease, ie, solitary or few detectable lesions (oligometastatic disease) and limited to a single organ, are more likely to benefit from local therapy than those with multiple metastases [4,5,6,8,9]. One exception is oligometastatic hepatic disease, as a few studies found that the presence or absence of extrahepatic disease (predominantly bone) did not affect long-term outcomes in patients undergoing hepatic resection [10-12].
Many of the studies that report successful surgery for metastatic disease, limited enrollment to patients with single-organ involvement.

●Long disease-free interval –A long disease-free interval (DFI), the period of time between the definitive treatment of the primary breast cancer and the development of distant oligometastasis, may portend an improved prognosis with local therapies [13-15]. The specific cutoff DFI that best discriminates between favorable and unfavorable outcomes is unclear, although an acceptable range is two to five years.

●High likelihood of complete resection – Careful preoperative evaluation is necessary to determine the likelihood that complete resection of the metastatic deposit is feasible. Positive margins are associated with worse outcomes in most but not all series [8, 16-19].

For patients with oligometastatic breast cancer undergoing local therapy, surgery, stereotactic body radiation therapy (SBRT), or both are primarily employed, though radiofrequency ablation (RFA, typically with surgery) is a one-time treatment that may be utilized as an alternative to SBRT for small hepatic tumors (<3 cm) that are not close to major vessels, biliary structures, or the diaphragm [20].

Brain — For most patients with brain metastases, a local approach such as resection, stereotactic radiosurgery (SRS), or whole-brain radiotherapy should be employed, often prior to or in conjunction with systemic therapy. When possible, SRS is used instead of whole-brain radiation to reduce toxicity.

Bone — Indications for local management of bone disease are fracture or impending fracture due to a metastasis, significant pain or decreased mobility of a joint, or spinal cord compression. In such cases, short-course palliative radiotherapy is commonly used. Pathologic fractures, pending fractures, or epidural spinal cord or nerve compression may require surgical intervention.

For asymptomatic patients without evidence of pending fracture, there is a limited role for resection as a means of extending survival. When metastatic breast cancer is confined to the bones, the natural history is usually characterized by an indolent course and good response to systemic therapy [21-23].

Lung — While most lung metastases are asymptomatic and do not require local intervention, those that are symptomatic or pose urgent risks to pulmonary function may benefit from local treatments. For some patients, pulmonary resection may be diagnostic as well as palliative in breast cancer patients, since a significant number of solitary pulmonary nodules in patients with a history of breast cancer are not breast cancer metastases [18,24,25].

Some experts additionally offer local treatment to a select subset of asymptomatic patients with multiple good-risk features, including solitary metastases (which occur in 10 to 25 percent of patients with metastatic breast cancer [9,26]), a DFI greater than 36 months, and hormone receptor-positive disease [4,8]. Some experts prefer to avoid the morbidity and mortality associated with such procedures, particularly in the absence of randomized data.

Liver — Hepatic metastases occur in over half of patients with metastatic breast cancer. They are most commonly a late development, associated with disseminated disease and a poorer prognosis than bone or soft tissue metastases. Only 5 to 12 percent of patients have isolated liver involvement [27-29]. Indications for local management of liver metastases include pain, bleeding that is refractory to medical therapy, or biliary obstruction. Some experts also offer local resection in carefully selected, asymptomatic patients, although there are no prospective data comparing local therapy with the administration of systemic treatment. Appropriate candidates include those with isolated liver involvement (5 to 12 percent of patients with metastatic breast cancer [27-29]), particularly those with hormone-positive disease, who have normal liver function, good performances status, and have had a long DFI [4,10,30].

Ovaries — Although the ovaries are a rare site for metastases from breast cancer [31,32], limited data suggest ovarian breast cancer metastases can appear many years following the initial diagnosis of breast cancer [33-36]. Surgical evaluation of an adnexal mass may be required to discriminate metastatic breast cancer from a primary ovarian cancer. Furthermore, for the premenopausal women with hormone-positive breast cancer, oophorectomy can provide a therapeutic effect, regardless of whether metastatic disease to the ovaries is present or not.

Other indications for local management of ovarian metastases may include pain or bleeding that is refractory to medical therapy, although in practice this presentation is rare.

Data are limited in regards to local management of ovarian metastases from breast cancer. In one series of 147 patients with metastatic disease to the ovary (8 percent of whom had a breast primary), the median overall survival after ovarian metastasectomy was 41 months [37]. For the entire series, massive intraoperative ascites, multiple metastases, and locally invasive disease were independent factors for a poorer overall survival.

Lack of overall survival benefit with local management of the primary tumor in metastatic breast cancer (June 2020)

Previous trials have shown mixed results on whether local treatment of the primary tumor in metastatic breast cancer improves survival. In the ECOG-ACRIN 2108 trial, approximately 250 patients with stage IV breast cancer who had been on systemic therapy for several months without progression were randomly assigned to continued systemic therapy versus local therapy (surgery, with or without radiation), followed by systemic therapy [1]. The three-year overall survival rate was 68 percent in both groups. Although local therapy reduced locoregional recurrence rates, quality of life outcomes were not improved. Given these and earlier results, we suggest systemic therapy without local management of the primary for most patients with metastatic breast cancer.

ΙΝ SUMMARY

Patients with metastatic breast cancer are unlikely to be cured of their disease by any means.

For the first presentation of metastatic disease, biopsy of the metastatic site should be performed to confirm the diagnosis and reestablish receptor status.

Patients who present with symptomatic metastases, eg, intractable pain, loss of organ function, or an oncologic emergency (eg, cord compression, mass effect due to brain metastases, pathologic fracture due to a bony metastasis), are appropriate candidates for urgent local intervention to relieve symptoms and preserve patient ability to function.

For asymptomatic patients, local management may be appropriate in select situations, for example, for the patient with an undiagnosed lung nodule or the patient with one or more brain metastases. Outside of these situations, some experts manage asymptomatic metastatic disease with systemic therapy only, while other experts may offer local management to select patients with multiple good-risk features, although this is not considered standard of care at this time.

1. Lee CG, McCormick B, Mazumdar M, et al. Infiltrating breast carcinoma in patients age 30 years and younger: long term outcome for life, relapse, and second primary tumors. Int J Radiat Oncol Biol Phys 1992; 23:969.
2. Vogel CL, Azevedo S, Hilsenbeck S, et al. Survival after first recurrence of breast cancer. The Miami experience. Cancer 1992; 70:129.
3. Leung AM, Vu HN, Nguyen KA, et al. Effects of surgical excision on survival of patients with stage IV breast cancer. J Surg Res 2010; 161:83.
4. Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst 2010; 102:456.
5. Fields RC, Jeffe DB, Trinkaus K, et al. Surgical resection of the primary tumor is associated with increased long-term survival in patients with stage IV breast cancer after controlling for site of metastasis. Ann Surg Oncol 2007; 14:3345.
6. Ly BH, Nguyen NP, Vinh-Hung V, et al. Loco-regional treatment in metastatic breast cancer patients: is there a survival benefit? Breast Cancer Res Treat 2010; 119:537.
7. Chua TC, Saxena A, Liauw W, et al. Hepatic resection for metastatic breast cancer: a systematic review. Eur J Cancer 2011; 47:2282.
8. Friedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases. Eur J Cardiothorac Surg 2002; 22:335.
9. Friedel G, Linder A, Toomes H. The significance of prognostic factors for the resection of pulmonary metastases of breast cancer. Thorac Cardiovasc Surg 1994; 42:71.
10. Pocard M, Pouillart P, Asselain B, et al. [Hepatic resection for breast cancer metastases: results and prognosis (65 cases)]. Ann Chir 2001; 126:413.
11. Yoshimoto M, Tada T, Saito M, et al. Surgical treatment of hepatic metastases from breast cancer. Breast Cancer Res Treat 2000; 59:177.
12. Sofocleous CT, Nascimento RG, Gonen M, et al. Radiofrequency ablation in the management of liver metastases from breast cancer. AJR Am J Roentgenol 2007; 189:883.
13. Dawood S, Broglio K, Gonzalez-Angulo AM, et al. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol 2008; 26:4891.
14. Gennari A, Conte P, Rosso R, et al. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104:1742.
15. Miao H, Hartman M, Bhoo-Pathy N, et al. Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study. PLoS One 2014; 9:e93755.
16. Raab R, Nussbaum KT, Behrend M, Weimann A. Liver metastases of breast cancer: results of liver resection. Anticancer Res 1998; 18:2231.
17. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997; 113:37.
18. McDonald ML, Deschamps C, Ilstrup DM, et al. Pulmonary resection for metastatic breast cancer. Ann Thorac Surg 1994; 58:1599.
19. Ludwig C, Stoelben E, Hasse J. Disease-free survival after resection of lung metastases in patients with breast cancer. Eur J Surg Oncol 2003; 29:532.
20. Veltri A, Gazzera C, Barrera M, et al. Radiofrequency thermal ablation (RFA) of hepatic metastases (METS) from breast cancer (BC): an adjunctive tool in the multimodal treatment of advanced disease. Radiol Med 2014; 119:327.
21. Briasoulis E, Karavasilis V, Kostadima L, et al. Metastatic breast carcinoma confined to bone: portrait of a clinical entity. Cancer 2004; 101:1524.
22. Sherry MM, Greco FA, Johnson DH, Hainsworth JD. Metastatic breast cancer confined to the skeletal system. An indolent disease. Am J Med 1986; 81:381.
23. Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 1998; 77:336.
24. Cahan WG, Castro EB. Significance of a solitary lung shadow in patients with breast cancer. Ann Surg 1975; 181:137.
25. Casey JJ, Stempel BG, Scanlon EF, Fry WA. The solitary pulmonary nodule in the patient with breast cancer. Surgery 1984; 96:801.
26. Planchard D, Soria JC, Michiels S, et al. Uncertain benefit from surgery in patients with lung metastases from breast carcinoma. Cancer 2004; 100:28.
27. Hoe AL, Royle GT, Taylor I. Breast liver metastases–incidence, diagnosis and outcome. J R Soc Med 1991; 84:714.
28. Atalay G, Biganzoli L, Renard F, et al. Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials. Eur J Cancer 2003; 39:2439.
29. Zinser JW, Hortobagyi GN, Buzdar AU, et al. Clinical course of breast cancer patients with liver metastases. J Clin Oncol 1987; 5:773.
30. Selzner M, Morse MA, Vredenburgh JJ, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000; 127:383.
31. Demopoulos RI, Touger L, Dubin N. Secondary ovarian carcinoma: a clinical and pathological evaluation. Int J Gynecol Pathol 1987; 6:166.
32. Alvarado-Cabrero I, Rodríguez-Gómez A, Castelan-Pedraza J, Valencia-Cedillo R. Metastatic ovarian tumors: a clinicopathologic study of 150 cases. Anal Quant Cytopathol Histpathol 2013; 35:241.
33. Quan ML, Fey J, Eitan R, et al. Role of laparoscopy in the evaluation of the adnexa in patients with stage IV breast cancer. Gynecol Oncol 2004; 92:327.
34. Abu-Rustum NR, Aghajanian CA, Venkatraman ES, et al. Metastatic breast carcinoma to the abdomen and pelvis. Gynecol Oncol 1997; 66:41.
35. Curtin JP, Barakat RR, Hoskins WJ. Ovarian disease in women with breast cancer. Obstet Gynecol 1994; 84:449.
36. Bigorie V, Morice P, Duvillard P, et al. Ovarian metastases from breast cancer: report of 29 cases. Cancer 2010; 116:799.
37. Li W, Wang H, Wang J, et al. Ovarian metastases resection from extragenital primary sites: outcome and prognostic factor analysis of 147 patients. BMC Cancer 2012; 12:278.

STYLIANOS GIASSAS
MEDICAL ONCOLOGIST
CHIEF OF THE 2nd ONCOLOGY CLINIC
IASO HOSPITAL

For women with early breast cancer, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, adjuvant endocrine therapy is the mainstay of systemic treatment. However, some of these cancers also stand to benefit from adjuvant chemotherapy. The magnitude of benefit from chemotherapy depends on the baseline risk of recurrence, which may be estimated from clinical features including the stage and grade of the tumor, as well as biologic features of the tumor, including gene expression.

All women with hormone receptor (HR)-positive, HER2-negative, non-metastatic breast cancer should be offered endocrine therapy.

Most instances of ER-positive, HER2-negative, node-negative breast cancer <1 cm, and all cancers ≤0.5 cm, have a sufficiently good prognosis with endocrine therapy alone, that they do not typically require adjuvant chemotherapy. At the other end of the risk spectrum, most women with stage III breast cancers will warrant adjuvant chemotherapy because of their risk of recurrence and the likely benefits of chemotherapy treatment. The majority of cases of ER-positive breast cancer fall in between these two extremes, and decisions regarding the addition of chemotherapy to adjuvant endocrine therapy are individualized based on patient and disease factors. Using gene expression profiles in women with ER-positive, HER2-negative disease in whom the decision regarding whether or not to use chemotherapy is unclear.

●We typically use these assays in patients with T1b to T3, node-negative tumors.

●Some also use them in patients with limited node-positive disease, although this practice is not uniform.

●However, we do not use these assays in patients with T1aN0 disease, as these patients have an excellent prognosis with endocrine therapy alone; nor do we generally use them in patients with stage III disease, as such patients typically have a high likelihood of benefit from chemotherapy. Exceptions might be made for patients with low-grade tumors and very limited lymph node involvement.

●Finally, as the primary role of these assays is to determine which clinical situations warrant chemotherapy, we do not use these assays in women who are not candidates for chemotherapy as the results would not alter management. This might include patients with absolute contraindications to chemotherapy due to baseline health concerns or frailty, or women who for other reasons will not consider chemotherapy. Gene expression profiles such as the Oncotype DX Recurrence Score (RS), EndoPredict, the Breast Cancer Index, and the Predictor Analysis of Microarray 50 (PAM50) intrinsic subtype assay have been developed to identify patients with such a low chance of recurrence that the absolute benefit of chemotherapy may not justify the risk of toxicities [1]. For the RS, prospective, randomized clinical trials do not demonstrate that women with low scores (less than 26) benefit from the addition of chemotherapy. By contrast, patients with higher scores on these assays have a sufficiently high risk of recurrence despite endocrine therapy that the addition of chemotherapy outweighs the risk of toxicities. Moreover, given that the response to treatment is not uniform among all cancers, these assays may identify those cancers that, based on their biologic profile, are likely to have an excellent outcome with endocrine therapy alone versus those in which the addition of chemotherapy would substantially reduce the risk of recurrence. The Oncotype DX 21-gene Recurrence Score (RS) is the best-validated prognostic assay and may identify patients who are most and least likely to derive benefit from adjuvant chemotherapy. At this time, it is indicated for women with node-negative, estrogen receptor (ER)-positive, HER2-negative breast cancer to determine the prognosis in patients recommended to proceed with at least a five-year course of endocrine therapy. The RS was developed by identifying the 250 most promising candidate genes described in the literature [2]. Investigators then used a reverse transcription polymerase chain reaction (RT-PCR)-based method for generating quantitative expression levels of these genes in fixed tissue from 447 patients collected from three datasets. A mathematic formula that includes 16 genes (plus 5 reference genes) was then generated to optimize prediction of distant relapse despite tamoxifen therapy. The sum of this calculation is known as the RS. The RS has been validated both as a prognostic as well as a predictive tool, by which to identify those patients with node-negative, hormone receptor (HR)-positive breast cancer whose prognosis is so favorable that the absolute benefit of chemotherapy is likely to be very low. Patients with ER-positive cancers that are node negative derive substantial benefit from chemotherapy if the 21-gene RS is high (typically >25). By contrast, if the score is low or midrange (≤25), there is no benefit to adding chemotherapy to endocrine treatment for women >50 years old, although younger women may experience some benefit [4,5,6].

The RS has been prospectively validated as a prognostic tool [6,7,8]. For example, the TAILORx study evaluated outcomes in 9719 women with HR-positive, HER2-negative, axillary node-negative breast cancer [4,6,7]. At nine years:

Among approximately 1600 women with low RS (≤10), all of whom received endocrine therapy without chemotherapy, the rate of invasive disease-free survival (DFS) at nine years was 84 percent [4].

●Among 6700 women with midrange RS (11 to 25), those randomly assigned to endocrine therapy alone had the same invasive DFS outcomes as those randomized to chemotherapy and endocrine therapy (83 versus 84 percent at nine years; hazard ratio [HR] 1.08, 95% CI 0.94-1.24) [4]. Rates of distant recurrence and overall survival (OS) were also similar between both groups (95 and 94 percent, for endocrine versus chemoendocrine therapy, respectively).

●Among almost 1400 women with a high RS (≥26), all of whom received chemotherapy (typically taxane- and/or anthracycline-containing regimens), the invasive disease free survival was 76 percent at nine years, and the rate of freedom from distant recurrence was 87 percent [4,9]. These results are better than what has been observed in other trials of endocrine therapy alone in similar patients (60 to 70 percent for invasive distant recurrence free survival rates, in the initial validation studies of the RS assay) [2,10]. Observational data also support an OS benefit for the addition of chemotherapy to endocrine therapy in this subset [11].

The overall results from TAILORx are similar to those from the PlanB trial [6], as well as earlier retrospective evaluations of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 clinical trial specimens (“prospective-retrospective” studies) [3]. In this trial of 651 patients, the addition of cyclophosphamide, methotrexate, plus fluorouracil (CMF) to tamoxifen resulted in a higher rate of distant DFS at 10 years among patients with a high RS (>30) compared with treatment with tamoxifen alone (88 versus 60 percent, respectively; relative risk 0.26, 95% CI 0.13-0.53) [3]. However, there was no evidence of a benefit with the addition of CMF among those with a low (<18) or an intermediate RS (19 to 30). It should be noted that the cutoff for low, intermediate, and high RS differed between the TAILORx and NSABP B-20 studies.

It has been argued that RS can be supplanted by improvements in pathologic grading and quantitative HR scoring. However, the NSABP B-20 study suggests that this may not be true. Even with central laboratory grading, 19 percent of high-grade tumors had a low RS (<18) and 5 percent of low-grade tumors had a high RS (>30). Further, the reproducibility of estrogen receptor (ER) and progesterone receptor (PR), as well as measures of proliferation such as immunohistochemistry (IHC) analysis of Ki-67, is poor between different laboratories.
Special considerations for those with intermediate RS — For women of any age whose tumors have a Recurrence Score (RS) ≤15, or for those >50 years with an RS ≤25, we recommend not using chemotherapy. Experts are divided in regards to the approach for patients ≤50 years with node-negative cancers with RS between 16 and 25. Some note that for most such patients they would not treat with chemotherapy, instead offering endocrine therapy alone and adding ovarian suppression for patients who are premenopausal. Other experts, however, offer chemotherapy to select women ≤50 years with RS 16 to 25, especially those who have either high-intermediate scores (21 to 25) or clinical risk factors, based on subset analyses of TAILORx discussed below [12].

In TAILORx, in the subset of women ≤50 years, endocrine therapy plus chemotherapy was associated with a lower rate of distant recurrence relative to endocrine therapy alone if the RS was >15 (at nine years, absolute percentage-point difference was 1.6 for RS 16 to 20, and 6.4 for RS 21 to 25). This benefit was not observed among women >50 years or in the overall population.

In subsequent reporting of TAILORx, clinical-risk stratification was used with the RS [13]. Low clinical risk was defined as tumors ≤3 cm and low grade, ≤2 cm and intermediate grade, or ≤1 cm and high grade. Tumors that did not fit any of these categories were high risk. The level of clinical risk was predictive for a benefit from chemotherapy in the subset of patients ≤50 years with an RS of 16 to 20. Among these women, there was a decrease in distant recurrence rates with versus without chemotherapy among those with high clinical risk (5.5 versus 12 percent, respectively), but not with low clinical risk (4.6 versus 4.8 percent, respectively). When analyzing the data for the entire group of women with intermediate RS (11 to 25), clinical risk did not predict benefit from chemotherapy, irrespective of age. Furthermore, among women ≤50 years with an RS of 21 to 25, the benefit of chemotherapy was similar in the low- and high-clinical-risk subgroups (absolute chemotherapy benefit of 6.4 versus 8.7 percent, respectively).

Among premenopausal women, the benefit from chemotherapy in patients with intermediate RS in TAILORx peaked for those at age 45 years, and the benefit was less for menopausal women. This trend raises the hypothesis that the benefit with chemotherapy in premenopausal women with intermediate RS may be due to chemotherapy-induced premature menopause. (Women younger than 45 years are unlikely to go into a permanent menopause because of chemotherapy and women older than 45 years are more likely to be entering menopause irrespective of chemotherapy. At an age of approximately 45 years, women receiving chemotherapy are most likely to experience menopause due to the chemotherapy)

Some experts support this hypothesis, and therefore offer ovarian suppression rather than chemotherapy for premenopausal women with intermediate RS scores. Others, however, believe that further data are needed, especially in light of the meta-analysis by the Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) with 100,000 randomized patients that does not show any effect of age (or size, grade, stage, or ER status) in the relative benefit from chemotherapy [14]. In a subsequent EBCTCG meta-analysis evaluating dose-intense/dose-dense versus standard every-three-weekly chemotherapy with 37,000 randomized patients, a similar relative benefit with chemotherapy was demonstrated, independent of age and clinical risk factors [15]. However, these meta-analyses were conducted in unselected patients, and not in the intermediate RS group, and pathologic assessment was not performed centrally. Given different interpretations of available data, we recognize that differences in approach among experts exist.

The Amsterdam 70-gene prognostic profile was one of the first gene expression arrays approved for commercial use (MammaPrint). Although it was originally approved for use with unfixed, frozen tissue, it has now been adapted for use with formalin-fixed, paraffin-embedded tissue. Based on the randomized trial discussed below (MINDACT), ASCO has suggested MammaPrint is one of several assays that might be used to determine prognosis for those with high clinical risk, HR-positive, HER2-negative breast cancer and no or limited (one to three) involved lymph nodes to inform decisions regarding withholding chemotherapy [12,16]. However, those with low clinical risk are unlikely to benefit from chemotherapy regardless of the results of this assay. For those with lymph node involvement and a low risk by Amsterdam genetic profile, counseling should be provided that a benefit from chemotherapy cannot be excluded, particularly in patients with more than one involved lymph node.

The 70-gene-profile was developed using a supervised DNA microarray analysis of gene expression arrays on frozen tissue from 98 primary breast tumors [17]. A mathematic model is used to calculate a score that stratifies patients as having a breast cancer with an associated poor prognosis or good prognosis.

The clinical validity of the 70-gene prognostic profile has been demonstrated in multiple studies [18-22]. Results from an international randomized trial, the Microarray in Node-Negative Disease

May Avoid Chemotherapy (MINDACT) trial, suggest that this genetic profile may identify subsets of patients who have a low likelihood of distant recurrence despite high-risk clinical features [22,23]. In this trial, 6693 women, approximately 80 percent of whom had lymph node-negative disease (and 20 percent of whom had one to three positive lymph nodes), underwent risk assessment by clinical criteria (using Adjuvant! Online) and by the 70-gene profile. Patients with discordant clinical and genomic predictions were randomly assigned to receive or not receive adjuvant chemotherapy. Among patients in the intention-to-treat population who had a high clinical risk of recurrence but a low risk by Amsterdam genetic profile, the five-year distant metastases-free survival rates were similar with and without chemotherapy (95.9 versus 94.4 percent, respectively; HR for distant metastasis or death 0.78, 95% CI 0.50-1.21), suggesting that this profile might identify patients with high clinical risk who may reasonably forego chemotherapy. However, it should be noted that the MINDACT study was not powered to exclude a benefit of chemotherapy.

Observational studies have similarly suggested that the 70-gene profile identifies patients with a low chance of recurrence, independent of nodal status, tumor grade, or hormone or HER2 receptor status [24].

There are more limited data for use of gene expression profiles in lymph node positive disease. Although both the Amsterdam 70-gene profile (MammaPrint) and Oncotype DX Recurrence Score (RS) have been evaluated in node positive disease, data for both are limited in this setting. The approach to incorporating gene expression profiles among those with lymph node involvement is variable among experts.

Some do not utilize gene expression profiles in the setting of lymph node involvement and recommend chemotherapy for any involved lymph nodes; others apply the RS for those with one to three lymph nodes and offer chemotherapy for more involved lymph nodes; while others apply RS to those with very limited nodal disease and offer chemotherapy to those with greater lymph node involvement. As such, one may opt for any of the following approaches, taking into account the pros and cons of each strategy.

●Administer chemotherapy to those with lymph node-positive disease.

If choosing this approach, one does not assess RS, as it does not change management. This approach may represent overtreatment and corresponding toxicity for the majority of patients in this category, in an effort to avoid missing patients who could have benefited if they were treated. Supporting rationale and data are as follows.

Adjuvant chemotherapy appears to provide a relative risk reduction in breast cancer mortality of approximately 20 to 30 percent, irrespective of size, stage, grade, estrogen receptor (ER) status, and whether patients were given endocrine therapy, according to the Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) meta-analyses of 100,000 and 37,000 patients [14,15]. Traditionally, lymph node positivity has been thought to confer a worsened prognosis, with lymph node-positive cancers having almost a twofold increase in recurrence rates compared with lymph node-negative cancers, in the absence of chemotherapy. Therefore, given the higher absolute likelihood of recurrence in those with lymph node-positive disease, the absolute benefit of chemotherapy is higher in this subset, and therefore chemotherapy is offered.

●Apply the RS for those with one to three positive nodes, using cutoffs as for those with node-negative disease, and recommend chemotherapy to those with >3 lymph nodes involved.

The rationale for this approach is that, in the modern era of more effective local and adjuvant therapy (eg, aromatase inhibitors, bisphosphonates), lymph node positivity might not confer the same degree of heightened risk as it once did, and that trials in node-negative cancers have not shown benefit from chemotherapy in tumors with low RS. As such, the absolute benefit of chemotherapy may be less than previously thought. Moreover, contrary to the EBCTCG meta-analysis discussed above, data from the neoadjuvant setting suggest that chemotherapy may not provide as much of a benefit for those with estrogen receptor (ER)-positive, HER2-negative disease [59]. This approach is included in the American Society of Clinical Oncology guidelines and in the National Comprehensive Cancer Network guidelines [10,60].

It stands to reason, therefore, that one may identify a subset of patients with lymph node-positive disease (as in those with node-negative disease) whose prognosis is so good that even if chemotherapy reduces the relative risk by 20 to 30 percent, the absolute benefit would still be no more that 1 to 3 percent. This is approximately the risk of severe or life-threatening toxicity of chemotherapy, and therefore it would be reasonable to avoid chemotherapy in such a subset, if it were able to be identified.

Supporting data for using the RS in lymph node-positive disease to identify this good-prognosis subset are limited, but are as follows. In the PlanB study, among 348 patients with RS ≤11 (approximately 40 percent of whom had one to three involved lymph nodes and the rest of whom had node-negative disease), the three-year progression-free survival was 98 percent, after a median follow-up of 35 months [14]. Although subset analysis for patients with node-positive, low-RS cancers was not provided, the overall results suggest that patients with limited nodal disease may be able to avoid chemotherapy if the RS is low. Additionally, a retrospective study evaluated tumor specimens from 367 postmenopausal women with node-positive, hormone receptor (HR)-positive breast cancer randomly assigned to tamoxifen alone or six cycles of cyclophosphamide, doxorubicin, and fluorouracil (CAF) followed by tamoxifen [61]. Compared with tamoxifen alone, the addition of CAF among women with a high RS (>30) resulted in improvements in disease-free and overall survival. By contrast, among postmenopausal women with node-positive tumors and a low RS (<18), no benefit for chemotherapy treatment was observed.

●Employ a hybrid approach, such as applying the RS only for those with a single positive node with <5 mm deposit and no extracapsular extension, using cutoffs as for those with node-negative disease, and recommend chemotherapy to those with more substantial lymph node involvement.

Although there are no specific data to support a hybrid approach and specific size of deposits, etc, this clinical stratification approach attempts to minimize the risks of toxicity with overtreatment, and the risks of recurrence associated with undertreatment.

The SWOG S1007 RxPONDER trial, which utilizes the RS to assign HR-positive, HER2-negative, node-positive patients to standard endocrine therapy with or without adjuvant chemotherapy, is ongoing and will inform our approach.

1. Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016; 34:1134.
2. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:2817.
3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24:3726.
4. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018; 379:111.
5. Pan H, Gray R, Braybrooke J, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 2017; 377:1836.
6. Gluz O, Nitz UA, Christgen M, et al. West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. J Clin Oncol 2016; 34:2341.
7. Sparano JA, Gray RJ, Makower DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373:2005.
8. Poorvu PD, Gelber SI, Rosenberg SM, et al. Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer. J Clin Oncol 2020; 38:725.
9. Sparano JA, Gray RJ, Makower DF, et al. Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial. JAMA Oncol 2020; 6:367.
10. Geyer CE Jr, Tang G, Mamounas EP, et al. 21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer. NPJ Breast Cancer 2018; 4:37.
11. Ma SJ, Oladeru OT, Singh AK. Association of Adjuvant Chemotherapy With Overall Survival in Patients With Early-Stage Breast Cancer and 21-Gene Recurrence Scores of 26 or Higher. JAMA Netw Open 2020; 3:e203876.
12. Henry NL, Somerfield MR, Abramson VG, et al. Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline. J Clin Oncol 2019; 37:1965.
13. Sparano JA, Gray RJ, Ravdin PM, et al. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. N Engl J Med 2019; 380:2395.
14. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012; 379:432.
15. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 2019; 393:1440.
16. Krop I, Ismaila N, Andre F, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 2017; 35:2838.
17. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415:530.
18. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002; 347:1999
19. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 2006; 98:1183.
20. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol 2010; 21:717.
21. Cardoso F, Van’t Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 2008; 26:729.
22. Piccart M, Rutgers E, van’t Veer L, et al. Primary analysis of the EORTC 10041/ BIG 3-04 MINDACT study: a prospective, randomized study evaluating the clinical utility of the 70-gene signature (MammaPrint) combined with common clinical-pathological criteria for selection of patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes. Cancer Res 2016; 76S: AACR #CT039.
23. Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016; 375:717.
24. Mook S, Knauer M, Bueno-de-Mesquita JM, et al. Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature. Ann Surg Oncol 2010; 17:1406.
25. 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; 384:164.
26. Goetz MP, Gradishar WJ, Anderson BO, et al. NCCN Guidelines Insights: Breast Cancer, Version 3.2018. J Natl Compr Canc Netw 2019; 17:118.

27. NCCN Clinical Practice Guideline in Oncology: Breast Cancer. Version 2.2017. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (Accessed on June 15, 2017).

28. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010; 11:55.

STYLIANOS GIASSAS
MEDICAL ONCOLOGIST
CHIEF OF THE 2nd ONCOLOGY CLINIC
IASO HOSPITAL

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, characterized by diffuse dermatologic erythema and edema (peau d’orange).

It accounts for 0.5 to 2 percent of invasive breast cancers diagnosed in the United States, but may be higher elsewhere [1,2]. As compared with locally advanced breast cancer, IBC is diagnosed at an earlier age (a median of 59 versus 66 years of age) [2]. The incidence of IBC is higher in black Americans compared with whites, and black women are diagnosed at a younger age [1,2]. Data on risk factors are limited and inconclusive [1].

Patients with inflammatory breast cancer (IBC) typically present with breast pain or a rapidly growing, self-diagnosed breast lump [3]. They may also report a tender, firm, or enlarged breast, or itching of the breast. On presentation, almost all women with IBC have lymph node involvement, and approximately one-third have distant metastases [4,6].

IBC is designated as T4d in the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging system [7].

Criteria must be met for diagnosis of IBC [8]:

Rapid onset of breast erythema, edema and/or peau d’orange, and/or warm breast, with or without an underlying palpable mass.
Duration of history no more than six months.
Erythema occupying at least one-third of the breast.
Pathologic confirmation of invasive carcinoma.

Multimodality therapy is standard for non-metastatic disease and includes neoadjuvant chemotherapy followed by mastectomy and postmastectomy radiation.

Neoadjuvant therapy, we utilize an anthracycline- and taxane-based dose-dense chemotherapy regime. Additional therapies depend on tumor receptor status:

Patients with IBC and human epidermal growth factor receptor 2 (HER2) overexpression should receive HER2-directed therapy (trastuzumab with pertuzumab) with neoadjuvant chemotherapy, although we avoid giving trastuzumab and anthracycline concurrently given the risk for cardiotoxicity. Trastuzumab with or without pertuzumab should be continued postoperatively for a total of one year of treatment if Pathologic Complete Response (PCR) is achieved. Otherwise if we do not receive PCR, adjuvant therapy will be 14 cycles with kadcyla.

For women with hormone receptor-positive disease, endocrine therapy should be initiated after completion of neoadjuvant therapy and continued in the adjuvant setting.

For patients with non-metastatic disease for whom surgery is not feasible even after the completion of a course of neoadjuvant chemotherapy, further efforts are directed at downstaging the tumor such that surgery may be performed. While data in this setting are limited, our approach is to utilize single-agent chemotherapies such as carboplatin, vinorelbine, or capecitabine for patients who are candidates for further chemotherapy. If patients are not candidates for further chemotherapy, or if the tumor continues to be chemoresistant after two or three lines of systemic treatment, we next utilize RT in attempts to decrease the extent of the disease. For patients whose tumor becomes resectable with these treatments, mastectomy and axillary node dissection should be pursued.