Recurrence of Breast Cancer Years After the Initial Tumor

Tamoxifen was approved by the FDA in 1977 to treat advanced breast cancer. In 1998, the Early Breast Cancer Trialists’ Cooperative Group published results showing that tamoxifen was effective in preventing breast cancer recurrence in patients whose tumors were estrogen receptor (ER)-positive or of unknown ER status,¹ which led to an expansion of the drug’s indication.² As effective as tamoxifen and other therapies have been, some breast tumors do recur. Despite the considerable scientific data and many successes in treating breast cancer, not much is known about recurrent breast tumors, other than that they can appear in almost any location in the body and at any time after remission is attained—even decades later.

A Cure or a Disease-Free Period?

The incidence of breast cancer has remained relatively stable since 2004.³ Declining incidence during the 1990s was attributed in part to lower utilization for estrogen replacement therapy for the treatment of menopausal symptoms.⁴

Alongside a stable level of breast cancer incidence, breast cancer deaths have dropped 34% since 1990.⁵ Better therapies have led to improved 5-year survival rates, which vary by race (90% for Caucasians and 79% for African Americans) and by stage at the time of diagnosis (Table 1). The relative survival rates at 10 and 15 years are 83% and 78%, respectively, for diagnosis at any stage.³ As a result, the number of breast cancer survivors is accumulating; about 3.1 million Americans are breast cancer survivors, defined as those patients who have completed active treatment.⁶

Despite these encouraging statistics, mortality is still high among patients who are initially diagnosed with advanced-stage breast cancer. For patients who are initially diagnosed with earlystage disease, recurrent breast cancer remains a principal cause of death,⁷ which may occur years afterward: the old philosophy that patients who do not demonstrate tumor recurrence for 5 years are “cured” has been replaced by the more precise observation that they remain “cancer-free.”

The Complexity of Recurrence

Location and Recurrence. Breast cancer survivors may live cancer-free for the remainder of their lives, but several other outcomes are possible. These include (1) living cancer-free for many years but having a late recurrence, (2) living cancer-free for many years but developing a second cancer, (3) having intermittent periods of treatment for active disease, or (4) living with cancer without any disease-free periods of time.⁶

Up to one-fifth of breast cancer survivors will experience a recurrence.⁸ The rate of recurrence at 10 years has declined since the 1980s and 1990s, when it ranged from 8% to 19%, to 2% to 7% in the past decade, depending on multiple factors. Whether a breast cancer survivor experiences a recurrence can depend on age at initial diagnosis, genetic background, what stage the cancer is at diagnosis, receptor type, histologic and nuclear grade of tumor, and how the original tumor was treated.^6,8

Recurrence, which may not necessarily be the same tumor reappearing, can be 1 of 3 types⁹:

• Local recurrence. Cancer recurrence is in the same localized area of the breast (ipsilateral) as the first tumor, or in the mastectomy scar. When breast cancer appears

in a different quadrant of the breast from the original tumor or in the other breast (contralateral), it is usually a new tumor.¹⁰

• Regional recurrence. The cancer is in nearby lymph nodes (eg, under the arm or around the collarbone).

• Distant recurrence. The cancer appears in another part of the body that is some distance from the original site (eg, bone marrow, lungs, liver, brain).

Part of the challenge is determining whether a second appearance of cancer is a recurrence or a new cancer. Regional and distant recurrence likely represent completely new tumors. For example, a recurrence that appears in the liver 10 years after the initial breast tumor is treated with agents appropriate to the tumor location (ie, using hepatic cancer therapies vs breast cancer therapies).

A small study in the mid-1990s found that 36% (N = 18) of the primary tumors that were ER-negative and progesterone receptor (PR)-positive were instead ER-negative and PR-negative in their recurrent form, while tumors that were initially receptor-negative remained so on recurrence. The authors concluded that the loss of ER expression in recurrent breast cancer may be the reason recurrent tumors respond poorly to endocrine therapy.¹¹ This finding suggested a distinct profile of the recurrent tumor. Patricia Ganz, MD, director, Cancer Prevention and Control Research, and director, Patients and Survivors Program Area, of the UCLA Jonsson Comprehensive Cancer Center, told Evidence-Based Oncology, “Breast cancers are made up of a mixture of cells. As a result, the recurrence may not be exactly like the primary tumor and may represent a subset of cells that disseminated. So we sometimes see tumors that were HER2 (human epidermal growth factor receptor)-negative initially show evidence of HER2 at recurrence. Likewise, tumors that were ER-positive

or -negative may change. The majority of recurrences—about 85%—are same as primary.”

Two-thirds of breast recurrences are identified as being a local recurrence, with the tumor recurring in the same breast in the same place or close to the original tumor; these cases are considered new growth of the old tumor. When there is a local recurrence, it usually occurs within 5 years of the initial breast cancer diagnosis.¹² After initial treatment, approximately 15% of breast cancer survivors will develop a second breast malignancy within 10 years,¹³ and about 40% of patients who experience recurrence have a regional recurrence in both the breast tissue or the chest wall, and in the lymph nodes. Fewer than 5% of patients have a recurrence that appears just in the lymph nodes, usually the:

• internal mammary (under the chest wall along the breastbone)

• infraclavicular (just below the collarbone)

• supraclavicular (base of the neck)

• axillary (underarm area) closest to the original tumor site

• axillary on the contralateral side (this is rarely seen)¹⁴

Age and Recurrence. Most women diagnosed with breast cancer are older than 65 years (median age, 61 years). However, one-fifth of those diagnosed are younger than 50 years.⁶ Past studies have shown that patients diagnosed at a younger age have a greater chance of recurrence than those diagnosed at an older age. Even with advances in therapy, younger women are more likely to experience a local recurrence (Figure).¹⁵

Breast Cancer—Receptor Type and Recurrence. Estrogen plays a major role in the development and progression of breast cancer. Seventy-five percent of breast cancer tumors express ER, and 55% express PR. HER2 also plays an important role in the development and progression of breast cancer. There are 5 molecular breast cancer subtypes, 4 of which are most commonly observed—luminal A, luminal B, HER2 type, and triple negative.^15,16 Many times, luminal A and luminal B are combined into 1 subtype, estrogen/progesterone-positive.

Patients with hormone receptor—positive tumors have a recurrence rate that is twice as high as those with hormone receptor–negative tumors at 5 years posttreatment.8 Women with ER-positive tumors have a greater risk of recurrence in later years than in the first 2 years.^17,18 Overall, ER-positive tumors are associated

with a long-term recurrence rate of 2% per year but are less likely to cause death from breast cancer than other tumor subtypes.¹⁶ Overall, patients with hormone receptor-positive tumors have the best outcomes.

ER-negative tumors mostly recur during the first 5 years, whereas the ER-positive tumors recur later.^17,18 By 15 years after diagnosis, the risk for recurrence is the same for both receptor types.⁷

Triple-negative breast cancers (TNBC) have a high risk of recurrence, especially for distant recurrences, compared with receptor-positive tumors.⁶ However, patients with TNBC who do not experience a recurrence within 5 years are more likely to remain cancer-free than patients with ER-positive tumors.¹⁶ A study by Miller and colleagues revealed that 15% of locoregional HER2-positive tumors recurred after 5 years, compared with 1% of luminal A tumors.¹⁹

Influence of Treatment Type on Recurrence. Evaluating a patient’s risk of breast cancer recurrence is further complicated by another factor: treatment of the initial cancer.¹⁹ The risk of distal recurrence is the same for patients having had a mastectomy or a lumpectomy plus radiation therapy.¹² Patients undergoing lumpectomy plus radiation therapy have an absolute risk reduction of 16% for any recurrence (locoregional or distant) within 10 years.²⁰ For patients who had a mastectomy, local recurrence will usually be observed 3 to 5 years after the surgery.⁸

When breast-conserving therapy approaches are used to treat early breast cancers, an annual incidence rate of local recurrence of 1.3% to 1.7% has been observed between 2 and 7 years following the initial treatment. The annual recurrence rate drops to 0.4% per year beginning at 10 years after initial treatment.⁷ Recurrence rates are similar for women with ER-positive and ER-negative original tumors when treated with breast conserving surgery or mastectomy.¹⁶ Including radiation therapy for patients with ER-positive tumors lowers their probability of an ipsilateral recurrence, compared with those who have ER-negative tumors. In cases of recurrence, patients with ER-positive tumors present better outcomes than those with ER-negative tumors.¹⁶

For patients with hormone receptor—positive tumors who are treated with endocrine therapy for 5 years after their initial therapy, 20% will have a recurrence by 10 years of completing their treatment, with twice as many having a recurrence during the first 5 years than in the second 5 years.8,21 In a study by Cadoo and associates,¹⁶ in half of the tumors that recurred in patients treated with tamoxifen, recurrence was observed between 6 and 15 years from diagnosis. A study by Davies and associates²¹ showed that continuing tamoxifen for 10 years, rather than 5 years, further reduced the risk for recurrence, especially after 10 years. Adjuvant endocrine therapy for hormone receptor—positive tumors reduces the risk of recurrence by up to half.²¹ The American Society of Clinical Oncology (ASCO) recently updated its guidelines to recommend 10 years of adjuvant endocrine therapy, rather than the 5 years previously recommended, to lower the risk of breast cancer recurrence and contralateral

breast cancer.²² More long-term studies will help guide the treatment of patients with hormone receptor—positive tumors to prevent recurrent breast cancer.

Patients with HER2-positive tumors have a greater chance of local recurrence than patients with ER-positive and HER2- negative tumors after both breast conserving surgery and mastectomy. These patients have a greater chance of a local recurrence than patients with triple-negative tumors; however, after a mastectomy, patients with TNBC seem to have a greater chance of local recurrence.¹⁶ Interestingly, patients with TNBC who have breast-conserving therapy with radiation have a lower risk of a local recurrence than those who have a mastectomy without radiation. These patients also have an increased risk for distal recurrence that peaks around 3 years, and

after 8 years, distal recurrences are typically not observed.¹⁶ Even after adjuvant chemotherapy, the risk for recurrence is the greatest in patients with HER2-positive and TNBC tumor subtypes.²³ Ganz added that this aspect has not been well studied. “Registries do not track this information accurately,” she said. “There is something called the Metastatic Breast Cancer Alliance, which is a consortium of advocacy groups trying to advocate for more information on this.”

Other Considerations. Presence of BRCA1 and BRCA2 gene mutations increase a woman’s risk for developing breast cancer. Individuals with these mutations are also at a higher risk for contralateral breast cancer after having been diagnosed and treated for an initial breast tumor compared with those who do not have such mutations (26% vs 3%).⁸

Other factors that appear to influence the risk of recurrence are levels of Ki-67, a cellular marker for cell proliferation, CK 5/6, p53 markers of basal-like tumors, and bcl-2, a proto-oncogene located on chromosome 18. Multiple genes that are potential markers for recurrence are included in the Oncotype DX (21 genes), Mammostrat (5 genes), MammaPrint (70 genes), and PAM50 (50 genes) genomic assays.24,25

Reducing the Risk for Recurrence. Many of the risks for the recurrence of breast cancer cannot be altered. However, lifestyle modifications and monitoring for the recurrence of breast cancer may be strategies that can reduce the risk of recurrence. In fact, key resource recommendations have been developed for appropriate survivorship care²⁶ (see Sidebar).

Trying to Better Understand Breast Cancer Recurrence

Advances in treatment and in understanding the genomics of breast cancer have led to improved 5-year survival in those patients diagnosed with and treated for breast cancer. However, we do not as yet have a thorough understanding of the patients who have a recurrence of their cancer or who develop another tumor.

According to information from provided by the American Cancer Society to Evidence-Based Oncology, there are no registries that accurately track characteristics of patients and their tumors, and who experiences a recurrence. A better understanding of whether patients at longterm risk for recurrence may redevelop their cancer or develop a new tumor may assist in reducing this risk further, and in optimizing the treatment options available to them.

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In the meantime, the concept of a “cure” in patients with breast cancer is more ambiguous than ever: patients in breast cancer survivorship programs with long-term remissions are increasingly being considered to have chronic disease, rather than acute episodic cancers. Ganz commented, “This is pretty common now for patients with HER2-positive disease or hormone receptor—positive disease.” The problem is that we really don’t know how many people can be addressed in this way. “Exact numbers are not available,” she said, “but we’re hoping to get a handle on this.” References

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