{"product_id":"is-invasion-required-for-breast-cancer-to-spread-a-review-of-the-evidence","title":"Is Invasion Required for Breast Cancer to Spread? A Review of the Evidence","description":"\u003cp\u003eThis review challenges the long-held belief that breast cancer must pass through an invasive stage before it can spread to other organs. The authors examined 50 years of cancer research and found that preventing invasive recurrences in the breast — through mastectomy or radiotherapy — does not reduce deaths from breast cancer. They propose an alternative model. In this model, a small pool of cancer stem cells has metastatic potential from the very beginning. These cells spread simultaneously to the breast, lymph nodes, and distant organs.\u003c\/p\u003e\n\n\u003ch1\u003eIs Invasion Required for Breast Cancer to Spread? A Review of the Evidence\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: The Traditional View of Breast Cancer Progression\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#systemic\"\u003eThe Systemic Nature of Breast Cancer\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#seer\"\u003eThe SEER Study: Mortality After DCIS\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#dcis-cancer\"\u003eIs DCIS a Cancer in Its Own Right?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#circulating\"\u003eCirculating Tumor Cells in DCIS\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#lymph-nodes\"\u003eLymph Node Involvement in DCIS\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#biopsy\"\u003eCould Biopsy Spread Cancer Cells?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#stage\"\u003eStage Distribution of Breast Cancer in the Population\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#three-women\"\u003eAre Primary Invasive Cancers and Local Recurrences Distinct?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#parallel\"\u003eThe Parallel Model of Breast Cancer\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Evidence\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Conclusions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eA review of 50 years of research challenges the traditional view that breast cancer must become invasive before it can spread to distant organs.\u003c\/li\u003e\n\u003cli\u003eIn a US registry study, mastectomy reduced local recurrence after DCIS by 75% but did not reduce breast cancer mortality; radiotherapy reduced recurrence by 50% without reducing mortality.\u003c\/li\u003e\n\u003cli\u003eIn a Swedish study of 96 DCIS patients who died of breast cancer, 15 developed distant metastases without a preceding invasive breast cancer.\u003c\/li\u003e\n\u003cli\u003eCirculating tumor cells were found in 13% to 25% of DCIS patients across six studies, at rates similar to those in invasive breast cancer.\u003c\/li\u003e\n\u003cli\u003eThe authors propose a parallel model where a small pool of cancer stem cells spreads simultaneously to the breast, lymph nodes, and distant organs; this hypothesis requires further testing.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: The Traditional View of Breast Cancer Progression\u003c\/h2\u003e\n\n\u003cp\u003eFor nearly a century, doctors believed that breast cancer starts in one location and spreads in a step-by-step manner. This conventional model, first proposed by Dr. William Halsted in the late 1800s held that cancer arises at a single spot in the breast. The cancer spreads locally within the breast tissue, then moves to the regional lymph nodes. Finally, the cancer disseminates to distant organs.\u003c\/p\u003e\n\n\u003cp\u003eThis sequential model shaped surgical practice for generations. Surgeons performed radical mastectomies (complete removal of the breast, chest muscles, and lymph nodes) because they believed that removing more tissue would prevent the cancer from spreading further.\u003c\/p\u003e\n\n\u003cp\u003eHowever, in the 1970s and 1980s, two landmark researchers — Fisher and Veronesi — challenged this view. They discovered that women treated with mastectomy (complete breast removal) had similar mortality rates. Women treated with breast-conserving surgery (lumpectomy, where only the tumor and some surrounding tissue are removed) also had similar mortality rates. This finding was celebrated as a breakthrough by patient advocacy groups and helped make lumpectomy the standard of care by the 1980s and 1990s.\u003c\/p\u003e\n\n\u003cp\u003eThe new \"systemic\" model suggested that in some cases, breast cancer had already spread beyond the breast before diagnosis. If that were true, removing more breast tissue would not improve survival — systemic treatment (such as chemotherapy or hormone therapy) would be necessary to eliminate cancer cells throughout the body.\u003c\/p\u003e\n\n\u003cp\u003eYet few researchers explored the full implications of this discovery. It had been known for some time that about one-third of women with breast cancer who undergo lumpectomy experience an invasive recurrence in the same breast. As expected, the risk of ipsilateral (same-side) invasive recurrence is much lower for women treated with mastectomy than for those treated with lumpectomy.\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, women who experience an in-breast invasive recurrence after lumpectomy face a much greater risk of dying from breast cancer than women who do not experience a recurrence. However, neither the American trial nor the Italian trial found that preventing a local invasive recurrence through mastectomy was associated with a decline in breast cancer mortality.\u003c\/p\u003e\n\n\u003cp\u003eTrials of radiotherapy after lumpectomy showed similar results. Radiotherapy was highly effective in preventing local recurrence, but its effect on breast cancer mortality was smaller than its effect on local invasive recurrence. These observations continue to puzzle researchers today and have profound implications that this review explores.\u003c\/p\u003e\n\n\u003ch2 id=\"systemic\"\u003eThe Systemic Nature of Breast Cancer\u003c\/h2\u003e\n\n\u003cp\u003eThe discovery that mastectomy and lumpectomy produce equivalent survival outcomes was a milestone in 20th-century breast cancer treatment. This finding suggested that breast cancer is a systemic disease from its earliest detectable stages in many patients.\u003c\/p\u003e\n\n\u003cp\u003eBy changing their practice to offer breast-conserving surgery, most surgeons tacitly endorsed Fisher's systemic model of breast cancer progression. However, few explored the theoretical implications of these observations.\u003c\/p\u003e\n\n\u003cp\u003eThe key observation is this: if preventing local invasive recurrence does not prevent death from breast cancer, then local recurrences may not be the source of distant metastases. This challenges the conventional sequential model and suggests that cancer cells may spread through multiple routes simultaneously.\u003c\/p\u003e\n\n\u003ch2 id=\"seer\"\u003eThe SEER Study: Mortality After DCIS\u003c\/h2\u003e\n\n\u003cp\u003eDuctal carcinoma in situ (DCIS) refers to the presence of abnormal cells within a breast duct or lobule. These abnormal cells have not breached the basement membrane. The basement membrane is a thin layer of tissue that separates the duct from surrounding breast tissue. DCIS is often described as \"stage 0\" breast cancer or a \"pre-invasive\" condition.\u003c\/p\u003e\n\n\u003cp\u003eThe authors conducted a study using the US SEER (Surveillance, Epidemiology, and End Results) Cancer Registry to examine rates of local recurrence and breast cancer mortality in patients with DCIS. The SEER registry is a large national database that tracks cancer cases across the United States.\u003c\/p\u003e\n\n\u003cp\u003eIn this study, among patients with DCIS, the risk of invasive local recurrence 10 years after treatment was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e1.3%\u003c\/strong\u003e for women treated with mastectomy\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e2.5%\u003c\/strong\u003e for women treated with lumpectomy plus radiation\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e4.9%\u003c\/strong\u003e for women treated with lumpectomy without radiation\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe risk of death from breast cancer after treatment was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e1.3%\u003c\/strong\u003e for women treated with mastectomy\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e0.8%\u003c\/strong\u003e for women treated with lumpectomy plus radiation\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e0.9%\u003c\/strong\u003e for women treated with lumpectomy without radiation\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese numbers reveal a striking paradox. Among DCIS patients, mastectomy reduced the risk of local recurrence by 75%, but it did not reduce the risk of dying from breast cancer. Similarly, radiotherapy after DCIS reduced the risk of local recurrence by 50%, but it did not reduce the risk of dying from breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eThis SEER analysis was preceded by the largest study of its kind, the EBCTG 2010 study. In that study, 3,729 women with DCIS were treated with breast-conserving surgery. These women were then randomly assigned to receive radiotherapy or no radiotherapy. Radiotherapy reduced the risk of ipsilateral invasive cancer by more than one-half (204 cases versus 92 cases). However, radiotherapy was associated with a small but non-significant increase in breast cancer mortality (44 deaths versus 52 deaths; hazard ratio 1.22).\u003c\/p\u003e\n\n\u003cp\u003eThe authors of the EBCTG study did not conclude that preventing local invasive recurrence fails to reduce mortality. Instead, they dismissed this incongruity somewhat cryptically, stating that \"the differences are not significant, chance seems to be a likely explanation for them.\"\u003c\/p\u003e\n\n\u003cp\u003eIn the SEER study, approximately one-half of the DCIS patients who died of breast cancer did not have an invasive cancer recorded prior to their death. This observation supports the position that DCIS is a cancer in its own right.\u003c\/p\u003e\n\n\u003cp\u003eSimilar findings were seen in a recent study of 9,799 DCIS cases from The Netherlands. In that study, the probability of developing an ipsilateral invasive breast cancer was much higher for women treated with lumpectomy (308 of 2,558; 12.0%) than for women treated with mastectomy (68 of 4,667; 1.5%). However, the absolute risks of breast cancer mortality at 10 years were similar for women treated with lumpectomy (2.7%; 95% confidence interval 2.1–3.4) and mastectomy (2.6%; 95% confidence interval 2.1–3.1).\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, of the 284 women who died of breast cancer in the Dutch study, only 43% had experienced a prior invasive breast cancer (in either breast).\u003c\/p\u003e\n\n\u003cp\u003eA large case-control study from Sweden reached similar conclusions. In that study, 96 women diagnosed with primary DCIS between 1992 and 2012 who later died of breast cancer were identified and compared with a group of 318 controls (women diagnosed with primary DCIS who were alive at the time of death of the corresponding case).\u003c\/p\u003e\n\n\u003cp\u003eTreatment by mastectomy or the addition of radiotherapy after lumpectomy was not associated with a lower risk of subsequent death from breast cancer. The odds ratio for death from breast cancer for patients treated with lumpectomy plus radiotherapy (versus lumpectomy alone) was 1.46 (95% confidence interval 0.81–5.63). The odds ratio for patients treated with mastectomy (versus lumpectomy alone) was 2.26 (95% confidence interval 1.29–4.06).\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, of the 96 cases, 15 developed distant metastases without a preceding ipsilateral or contralateral invasive breast cancer. The authors reported that all medical records for cases and controls were retrieved and that follow-up of subsequent breast events and causes of death was complete. They suggested that these results may indicate that some DCIS has an inherent potential for metastatic spread.\u003c\/p\u003e\n\n\u003ch2 id=\"dcis-cancer\"\u003eIs DCIS a Cancer in Its Own Right?\u003c\/h2\u003e\n\n\u003cp\u003eThe appearance of a local invasive recurrence after DCIS is predictive of a large increase in the risk of dying of breast cancer. Some researchers argue that this supports the notion that the invasive recurrence is the true malignancy.\u003c\/p\u003e\n\n\u003cp\u003eFor example, Wapnir and colleagues reported that after local invasive recurrence in a patient with DCIS, the mortality rate increases 7.1 times. In the SEER study, invasive recurrence increased subsequent breast cancer mortality 18.1 times.\u003c\/p\u003e\n\n\u003cp\u003eHowever, this does not necessarily mean that the recurrence itself has metastatic potential. The recurrence could simply be a marker of aggressive disease biology. To illustrate this point, the authors offer an analogy. Men with nicotine-stained teeth have a much higher risk of dying of lung cancer than men with unstained teeth. This risk is perhaps 20-fold higher. This does not imply that brushing your teeth prevents lung cancer.\u003c\/p\u003e\n\n\u003cp\u003eAnother criticism raised against the SEER study and the message that DCIS could be fatal in its own right was that pathology is an inexact science. Some argued that the 3% of women who died of breast cancer probably had cancers with missed foci of micro-invasion, and hence, many invasive breast cancers were misclassified as DCIS.\u003c\/p\u003e\n\n\u003cp\u003eIn the SEER data set, there were 13,489 cases of DCIS with micro-invasion that were excluded from the original analysis. In SEER, the 10-year mortality rate from breast cancer was 2.8% for patients with DCIS with micro-invasion and 1.4% for women with DCIS without micro-invasion.\u003c\/p\u003e\n\n\u003cp\u003eIf the mortality of DCIS patients was confined to the subgroup of patients with micro-invasion, then 50% of DCIS patients would have to have occult micro-invasion to generate these observed rates. This would challenge the concept of DCIS as a discrete category.\u003c\/p\u003e\n\n\u003cp\u003eOthers expressed the opinion that DCIS is highly heterogeneous and that we cannot assume all women with DCIS form a single category. Perhaps 3% of cases of DCIS are, in fact, cancer, but these few cases are outliers and the vast majority of cases of DCIS (97%) are not cancer. By the same logic, one could claim that more than 90% of stage I breast cancers are not cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"circulating\"\u003eCirculating Tumor Cells in DCIS\u003c\/h2\u003e\n\n\u003cp\u003eBreast cancer dissemination can occur in pre-invasive stages of tumor progression. Support for this notion comes from the consistent finding of circulating tumor cells in the peripheral blood or bone marrow of patients with DCIS.\u003c\/p\u003e\n\n\u003cp\u003eIn six studies (with a range of 19 to 404 patients), between 13% and 25% of DCIS patients were found to have circulating tumor cells. It has been proposed that such cells derive from an occult (micro)-invasive lesion within DCIS. However, there is no difference in the frequency of circulating tumor cells in patients with DCIS compared to those with frank invasive breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eIn one study, disseminated tumor cells were detected in the bone marrow of 25% of 24 patients with pure DCIS and in 20% of 56 patients with non-metastatic invasive cancer (p = 0.57). In another study, circulating tumor cells were detected in the peripheral blood of 18.7% of 48 patients with pure DCIS and in 18.8% of 404 patients with non-metastatic invasive breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eThe clinical significance of detecting circulating tumor cells in patients with DCIS is still unclear. However, this finding raises the important point that cells may enter circulation prior to passing the basement membrane.\u003c\/p\u003e\n\n\u003ch2 id=\"lymph-nodes\"\u003eLymph Node Involvement in DCIS\u003c\/h2\u003e\n\n\u003cp\u003eSeveral pathology studies have reported that a significant proportion of patients with a final diagnosis of pure DCIS have positive lymph nodes (about 3%). Nodal disease is postulated to indicate that occult invasion must be present in the primary tumor.\u003c\/p\u003e\n\n\u003cp\u003eBased on this assumption, the SEER classification automatically assigns cases of DCIS with lymph node metastasis to stage II or stage III. However, this prejudges the importance of the observations. There is now consistent evidence that some women with confirmed DCIS will have positive lymph nodes, even when comprehensive tissue sectioning reveals no occult invasion.\u003c\/p\u003e\n\n\u003cp\u003eThis observation is important and reflects a need to re-examine the association between non-invasive tumors and lymph node involvement.\u003c\/p\u003e\n\n\u003cp\u003eA possible mechanism by which DCIS cells may enter circulation without breaching the basement membrane has been described for mucinous DCIS. In a study of 36 patients with mucinous DCIS, small vessels were identified within the lumen duct in 26 cases (72%). The authors propose an alternative pathway for invasion whereby intra-ductal mucin production promotes neovascularization (growth of new blood vessels). However, this is a rare subtype of DCIS.\u003c\/p\u003e\n\n\u003ch2 id=\"biopsy\"\u003eCould Biopsy Spread Cancer Cells?\u003c\/h2\u003e\n\n\u003cp\u003eA further possibility for the induction of metastases in patients with DCIS may be the iatrogenic (treatment-caused) dissemination of tumor cells at the time of pre-operative biopsy.\u003c\/p\u003e\n\n\u003cp\u003eIncisional biopsy, including the diagnostic core needle biopsy, has been associated with seeding of tumor cells into the circulation and has been hypothesized to increase the risk of metastatic disease. Seeding of the needle tract and mechanical displacement of cells into the lymphatic or vascular system has been documented in DCIS, but the clinical implications are not known.\u003c\/p\u003e\n\n\u003cp\u003eLiebens and colleagues reviewed the clinical significance of malignant epithelial cell displacement after core needle biopsy in breast cancer patients. Tumor cell displacement on surgical specimens occurred in 22% of patients overall, with similar rates seen for DCIS and invasive breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eHowever, tumor cell displacement was seen less frequently as the interval between biopsy and surgical excision lengthened. This suggests that seeded cells do not survive displacement. No studies to date have documented a survival disadvantage with pre-operative biopsy.\u003c\/p\u003e\n\n\u003cp\u003eFrom these observations, the authors conclude that the patterns of local recurrence and mortality after DCIS and after primary invasive breast cancer are qualitatively similar and differ only by degree.\u003c\/p\u003e\n\n\u003cp\u003eFisher and Veronesi pointed out that after primary invasive cancer, preventing local recurrence (by mastectomy versus lumpectomy) does not reduce mortality. If it did, then mastectomy would be recommended for all patients. The same holds true for DCIS.\u003c\/p\u003e\n\n\u003cp\u003eBy extension, an in-breast invasive event following a diagnosis of DCIS might better be described as a local invasive recurrence than as a new primary cancer. However, what has been accepted for invasive cancer has not been accepted for DCIS.\u003c\/p\u003e\n\n\u003cp\u003eTo summarize the authors' argument: if an in-breast invasive recurrence observed after DCIS were a primary breast cancer, then preventing it should also prevent subsequent metastases. These subsequent metastases could potentially be fatal. If so, preventing the recurrence should prevent at least some deaths. However, preventing the invasive in-breast recurrence after DCIS did not result in fewer deaths. Therefore, the recurrence is not a primary invasive cancer. Therefore, the DCIS has inherent malignant potential.\u003c\/p\u003e\n\n\u003cp\u003eThe authors note that their position has not been widely accepted. Most commentators continue to describe DCIS as a precursor lesion with little or no inherent malignant potential.\u003c\/p\u003e\n\n\u003ch2 id=\"stage\"\u003eStage Distribution of Breast Cancer in the Population\u003c\/h2\u003e\n\n\u003cp\u003eOur current view of the natural history of breast cancer is the product of incremental understanding developed over the last century. This understanding is based on a chronological sequence of observations about the timing of breast cancers and cancer metastases.\u003c\/p\u003e\n\n\u003cp\u003eThe various states and stages of breast cancer have revealed themselves slowly. This has happened as techniques of imaging have been refined. These techniques include gross-level imaging through mammography and microscopic-level imaging through histology and immunohistochemistry.\u003c\/p\u003e\n\n\u003cp\u003ePrior to the 20th century, breast cancer patients often presented with extensive local disease, which might involve infection and ulceration. Later, it was recognized that an asymptomatic mass detected on physical examination might be cancerous and that this suspicion could be confirmed by biopsy and histology.\u003c\/p\u003e\n\n\u003cp\u003eThis was the state of the art of breast cancer detection and diagnosis until late in the 20th century, when mammography screening became commonplace. In the late 1970s, small intra-ductal lesions were seen in pathology specimens with increasing frequency, and these were described as DCIS. At this time, DCIS was considered to be a special histologic subgroup of breast cancers rather than an early phase of breast cancer itself.\u003c\/p\u003e\n\n\u003cp\u003eThe relative numbers of women in the entire population with DCIS, with organ-confined breast cancer, and with disseminated breast cancer at a given time can be crudely estimated. This estimate can be made by the proportions of cancers diagnosed at various stages.\u003c\/p\u003e\n\n\u003cp\u003eIn the absence of screening, there are few cases of DCIS. Ninety percent of cases are diagnosed at stages I–III, and about 10% are diagnosed at stage IV.\u003c\/p\u003e\n\n\u003cp\u003eFor screen-detected breast cancers, the distribution shifts:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e20%\u003c\/strong\u003e are DCIS (stage 0)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e75%\u003c\/strong\u003e are stages I–III\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e5%\u003c\/strong\u003e are stage IV\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eAt autopsy, most cases are in situ. We can speculate on the actual distribution of cancers in the entire underlying population of women, both detected and undetected. This speculation can be based on post-mortem pathology studies or on new and highly sensitive screening modalities, such as MRI.\u003c\/p\u003e\n\n\u003cp\u003eThe likelihood of a cancer being detected, if present, depends on the size of the cancer, its palpability, the frequency of screening, and the sensitivity of the particular screening test. We can assume that every breast cancer passes through an undetectable phase at which time it is missed by our most sensitive screening tools.\u003c\/p\u003e\n\n\u003cp\u003eFor this reason, the observed ratio of 1–3 for DCIS to invasive cancers in clinic patients is probably an underestimate of the true ratio.\u003c\/p\u003e\n\n\u003ch2 id=\"three-women\"\u003eAre Primary Invasive Cancers and Local Recurrences Distinct?\u003c\/h2\u003e\n\n\u003cp\u003eThe authors present a thought experiment involving three women to illustrate their hypothesis. Consider three women, born in the same year in the same city.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eWoman A\u003c\/strong\u003e is worried about getting breast cancer. Even though she has no family history or any dominant risk factor, she decides to have a bilateral prophylactic mastectomy (preventive removal of both breasts) at age 30. She is now age 60 and is doing well with no cancer history. Unbeknownst to her, she was destined to develop DCIS at age 40, but this was pre-empted by the preventive surgery.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eWoman B\u003c\/strong\u003e opts not for surgery but goes for annual mammography. At age 40, she has an abnormal mammogram, and a small focus of DCIS is discovered upon biopsy. She has breast-conserving surgery. The margins are clear. Despite this, 5 years later, she is diagnosed with an invasive recurrence in her breast, 2 cm in diameter. The nodes are clear.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eWoman C\u003c\/strong\u003e does not go for mammography but instead goes to her doctor for an annual physical exam. At age 45, the physician feels a lump, and the biopsy reveals a stage I invasive breast cancer, 2 cm in size. Nodes are clear.\u003c\/p\u003e\n\n\u003cp\u003eIn their medical synopses, Woman B is described as having DCIS with an invasive recurrence, and Woman C is described as having primary invasive breast cancer. What we neglect to mention in this thought experiment is that these three are the same woman.\u003c\/p\u003e\n\n\u003cp\u003eBefore mammographic screening was introduced, women typically presented with invasive breast cancer. If they passed through an earlier stage of DCIS, no one was the wiser. After mammography was introduced, the incidence of DCIS rose by 500% between 1983 and 2003.\u003c\/p\u003e\n\n\u003cp\u003eIf we assume the underlying incidence of DCIS over time was stable, then the increase was the consequence of more extensive screening. The proportion of cases of invasive breast cancer with a prior record of DCIS grew steadily from 1980 to 2012.\u003c\/p\u003e\n\n\u003cp\u003eA woman who is diagnosed with DCIS and an ipsilateral invasive recurrence nowadays would likely have been diagnosed with primary invasive breast cancer in 1970.\u003c\/p\u003e\n\n\u003cp\u003eIn this light, the authors propose that in-breast invasive recurrences after DCIS and primary invasive breast cancers are two facets of the same condition. These two facets differ according to when they are detected.\u003c\/p\u003e\n\n\u003ch2 id=\"parallel\"\u003eThe Parallel Model of Breast Cancer\u003c\/h2\u003e\n\n\u003cp\u003eBased on their review of the evidence, the authors propose an alternative model of breast cancer progression. They call this the \"parallel\" model, as opposed to the conventional \"sequential\" model.\u003c\/p\u003e\n\n\u003cp\u003eIn the parallel model, there is a small pool of cancer stem cells that have metastatic potential from their inception. These cells disseminate synchronously (at the same time) through several routes:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eTo the breast stroma (the connective tissue of the breast)\u003c\/li\u003e\n\u003cli\u003eTo the lymph nodes\u003c\/li\u003e\n\u003cli\u003eTo distant organs\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eCancer cells that disseminate to the breast give rise to cells that make up the bulk of the tumor mass. However, these cells are not the source of the distant metastases.\u003c\/p\u003e\n\n\u003cp\u003eThis model helps explain several puzzling observations:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003ePreventing local recurrence through mastectomy or radiotherapy does not reduce breast cancer mortality.\u003c\/li\u003e\n\u003cli\u003eDCIS can be fatal even without evidence of invasion.\u003c\/li\u003e\n\u003cli\u003eCirculating tumor cells can be found in patients with DCIS.\u003c\/li\u003e\n\u003cli\u003eLymph nodes can be positive in patients with pure DCIS.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe relationship between DCIS and death can be represented as two separate pathways. One pathway leads from DCIS to local recurrence. Another pathway leads from DCIS to distant recurrence. There is no analogous pathway from local recurrence to distant recurrence.\u003c\/p\u003e\n\n\u003cp\u003eThis leads logically to the conclusion that local recurrences do not have the potential to metastasize. If a local recurrence could metastasize, then a local recurrence would be a life-threatening event. However, preventing local recurrence after DCIS does not prevent death. Therefore, the local recurrence does not metastasize.\u003c\/p\u003e\n\n\u003cp\u003eThe same logic holds true for local recurrences following primary invasive breast cancers.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis review has several important implications for patients with DCIS or invasive breast cancer.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFor patients with DCIS:\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eDCIS should be considered a cancer in its own right, not merely a precursor lesion.\u003c\/li\u003e\n\u003cli\u003eThe choice between mastectomy and lumpectomy with radiation does not appear to affect overall survival, even though mastectomy is more effective at preventing local recurrence.\u003c\/li\u003e\n\u003cli\u003eAn invasive recurrence in the breast after DCIS treatment is better characterized as a local recurrence than as a new primary cancer.\u003c\/li\u003e\n\u003cli\u003ePatients should discuss the risks and benefits of different treatment options with their healthcare providers, understanding that preventing local recurrence may not translate into improved survival.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eFor patients with invasive breast cancer:\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eThe finding that mastectomy and lumpectomy produce equivalent survival outcomes supports the view that breast cancer is often a systemic disease from early stages.\u003c\/li\u003e\n\u003cli\u003ePreventing local recurrence through more extensive surgery does not appear to reduce the risk of death from breast cancer.\u003c\/li\u003e\n\u003cli\u003eSystemic treatments (such as chemotherapy, hormone therapy, and targeted therapies) are important because they address cancer cells that may have already spread beyond the breast.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eFor understanding breast cancer biology:\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eCancer cells may spread through multiple routes simultaneously, not in a strict sequence.\u003c\/li\u003e\n\u003cli\u003eThe presence of circulating tumor cells in DCIS patients suggests that dissemination can occur before invasion through the basement membrane.\u003c\/li\u003e\n\u003cli\u003eLymph node involvement in DCIS may not always indicate occult invasion.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Evidence\u003c\/h2\u003e\n\n\u003cp\u003eThe authors acknowledge several limitations and areas of ongoing debate.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePathology limitations:\u003c\/strong\u003e Some researchers argue that pathology is an inexact science. They suggest that the small percentage of women with DCIS who die of breast cancer may have had cancers with missed foci of micro-invasion. If this were true, many invasive breast cancers would have been misclassified as DCIS.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eHeterogeneity of DCIS:\u003c\/strong\u003e DCIS is a highly heterogeneous condition. Not all cases of DCIS may have the same malignant potential. Some researchers argue that we cannot assume all women with DCIS form a single category.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinical significance of circulating tumor cells:\u003c\/strong\u003e The clinical significance of detecting circulating tumor cells in patients with DCIS is still unclear. It is not known whether these cells can actually establish metastases or whether they are cleared by the immune system.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eBiopsy-related cell displacement:\u003c\/strong\u003e While tumor cell displacement has been documented after core needle biopsy, no studies to date have documented a survival disadvantage with pre-operative biopsy. The clinical implications of this finding remain unknown.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcceptance of the parallel model:\u003c\/strong\u003e The authors note that their position has not been widely accepted. Most commentators continue to describe DCIS as a precursor lesion with little or no inherent malignant potential.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Conclusions\u003c\/h2\u003e\n\n\u003cp\u003eThe authors conclude that the conventional sequential model of breast cancer progression does not fully explain the observed patterns of recurrence and mortality.\u003c\/p\u003e\n\n\u003cp\u003eThey propose that breast cancer dissemination occurs through parallel pathways from a small pool of cancer stem cells with metastatic potential from their inception. These cells spread simultaneously to the breast, lymph nodes, and distant organs.\u003c\/p\u003e\n\n\u003cp\u003eThis model has important implications for treatment and research:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eTreatment focus:\u003c\/strong\u003e The goal of treatment should be to eliminate systemic disease, not just local disease. This supports the use of systemic therapies in appropriate patients.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDCIS management:\u003c\/strong\u003e DCIS should be recognized as a condition with inherent malignant potential. Treatment decisions should account for this understanding.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eResearch directions:\u003c\/strong\u003e Further research is needed to identify and target the cancer stem cells responsible for metastatic spread.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePatient communication:\u003c\/strong\u003e Patients should be informed that preventing local recurrence may not prevent distant recurrence or death.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe authors emphasize that their hypothesis requires further testing and validation. However, they believe the evidence strongly supports a re-examination of the conventional model of breast cancer progression.\u003c\/p\u003e\n\n\u003cp\u003eFor patients, the key message is that breast cancer is a complex disease that can spread through multiple routes. Treatment decisions should be made in consultation with healthcare providers, taking into account the individual patient's circumstances and the latest evidence.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eDoes breast cancer have to become invasive before it can spread?\u003c\/h3\u003e\n\u003cp\u003eA review of 50 years of research challenges the traditional view that breast cancer must pass through an invasive stage before spreading. The authors propose that a small pool of cancer stem cells may have metastatic potential from the beginning, spreading simultaneously to the breast, lymph nodes, and distant organs. This parallel model is a hypothesis requiring further testing.\u003c\/p\u003e\n\u003ch3\u003eIf I have DCIS, does choosing mastectomy over lumpectomy improve my survival?\u003c\/h3\u003e\n\u003cp\u003eIn a large US registry study, mastectomy reduced the risk of local recurrence after DCIS by 75%, but it did not reduce the risk of dying from breast cancer. Radiotherapy after DCIS reduced local recurrence by 50% without reducing breast cancer mortality. The choice between mastectomy and lumpectomy with radiation did not appear to affect overall survival.\u003c\/p\u003e\n\u003ch3\u003eCan DCIS spread to other parts of the body even though it is non-invasive?\u003c\/h3\u003e\n\u003cp\u003eYes, research suggests it may. In a Swedish case-control study of 96 women with DCIS who died of breast cancer, 15 developed distant metastases without a preceding invasive breast cancer in either breast. Additionally, circulating tumor cells have been found in 13% to 25% of DCIS patients across six studies, though their clinical significance remains unclear.\u003c\/p\u003e\n\u003ch3\u003eWhat does it mean if I have an invasive recurrence after DCIS treatment?\u003c\/h3\u003e\n\u003cp\u003eAn invasive recurrence in the breast after DCIS treatment is better characterized as a local recurrence than as a new primary cancer. In a US registry study, such a recurrence increased subsequent breast cancer mortality 18.1 times, but preventing it through mastectomy or radiotherapy did not reduce deaths. This suggests the recurrence may be a marker of aggressive disease biology.\u003c\/p\u003e\n\u003ch3\u003eAre circulating tumor cells found in DCIS patients, and what do they mean?\u003c\/h3\u003e\n\u003cp\u003eYes, circulating tumor cells have been detected in 13% to 25% of DCIS patients across six studies. Their frequency is similar to that in patients with invasive breast cancer. However, the clinical significance is still unclear; it is not known whether these cells can establish metastases or are cleared by the immune system.\u003c\/p\u003e\n\u003ch3\u003eCould a breast biopsy cause cancer cells to spread?\u003c\/h3\u003e\n\u003cp\u003eTumor cell displacement after core needle biopsy has been documented in 22% of patients overall, with similar rates for DCIS and invasive breast cancer. However, displacement was seen less frequently as the time between biopsy and surgery lengthened, suggesting seeded cells do not survive. No studies to date have documented a survival disadvantage with pre-operative biopsy.\u003c\/p\u003e\n\u003ch3\u003eWhat are the treatment implications of this new model of breast cancer?\u003c\/h3\u003e\n\u003cp\u003eThe review suggests that the goal of treatment should be to eliminate systemic disease, not just local disease, supporting the use of systemic therapies in appropriate patients. It also recommends that DCIS be recognized as having inherent malignant potential. Patients should be informed that preventing local recurrence may not prevent distant recurrence or death.\u003c\/p\u003e\n\u003ch3\u003eI was just diagnosed with DCIS and my surgeon recommends mastectomy — should I get a second opinion before deciding between mastectomy and lumpectomy with radiation?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is reasonable when weighing mastectomy against lumpectomy with radiation for DCIS. Mastectomy lowers the risk of local invasive recurrence, yet the risk of dying from breast cancer is similar across treatments: 1.3% after mastectomy, 0.8% after lumpectomy plus radiation, and 0.9% after lumpectomy alone. Because preventing local recurrence does not appear to reduce breast cancer mortality, an independent review can help clarify whether more extensive surgery is necessary for your situation. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Is invasion a necessary step for metastases in breast cancer\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Steven A. Narod and Victoria Sopik\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Women's College Research Institute, Women's College Hospital, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Breast Cancer Research and Treatment (2018) 169:9–23\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.1007\/s10549-017-4644-3\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eReceived:\u003c\/strong\u003e 18 November 2017\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAccepted:\u003c\/strong\u003e 23 December 2017\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublished online:\u003c\/strong\u003e 20 January 2018\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eKeywords:\u003c\/strong\u003e Breast cancer, DCIS, Invasion, Metastasis, Death\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. The original article is an open-access publication distributed under the terms of the Creative Commons Attribution 4.0 International License.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807396806812,"sku":null,"price":0.0,"currency_code":"KRW","in_stock":true}],"url":"https:\/\/diagnosticdetectives.kr\/products\/is-invasion-required-for-breast-cancer-to-spread-a-review-of-the-evidence","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}